Galacturonides of the anti-inflammatory pregnane series



United States Patent 3,206,359 GALACTURONIDES OF THE ANTI-INFLAMMA- TORY PREGNANE SERIES Lewis H. Sarett, Princeton, Robert G. Strachan, Summit,

and Ralph F. Hirschmann, Scotch Plains, N.J., assignors to Merck & Co., Inc., Rahway, N.J., a corporation of New Jersey No Drawing. Filed Feb. 18, 1963, Ser. No. 259,383 18 Claims. (Cl. 167-58) This invention is converned generally with novel steroid galacturonides and processes of preparing the same. More particularly, it relates to galacturonide derivatives of Ring A unsaturated 11,17-bis-oxygenated-20-keto-steroids of the anti-inflammatory pregnane series; With processes of preparing these galacturonide compounds; and with pharmaceutical compositions containing them. These novel Ring A unsaturated 11,17-bis-oxygenated-20- keto-pregnane galacturonides including the preferred Ring A unsaturated 11,17-bis-oxygenated-ZO-keto-Z1-hydroxypregnane 21-galacturonides, while possessing the anti-inflammatory activity characteristic of cortisone, differ from cortisone, hydrocortisone, and their A -derivatives, prednisone and prednisolone, in being remarkably free from the ulcerogenic action, adrenal atrophy, thymus involution and body-weight-loss side-effects which have resulted from prolonged administration of the aforementioned anti-inflammatory steroids.

The novel 21-galacturonides of Ring A unsaturated 11,- 17-bis-oxygenated-20-keto-2l hydroxy steroids of the antiinflammatory pregnane series, preferred embodiment of the present invention, may be chemically represented as follows:

wherein ZCH stands for the radical of a Ring A unsaturated 11,17 bis-oxygenated-20-keto-2l-desoxy-steroid of the pregnane series in which one of the hydrogens at C-21 has been replaced by the galacturonide moiety.

These preferred 2l-galacturonides of Ring A unsaturated 1l,17-bis-oxygenated-20-keto-steroids of the pregnane series may be prepared by reacting the corresponding steroid ZI-free alcohol compound with an alkyl (tri-O-acyl- 0c D galactopyranosyl bromide) uronate, preferably methyl (tri-O-acetyl-a-D-galactopyranosyl bromide)-uromate, to form the corresponding alkyl (steroid-Zl-yl tri- O-acyl-B-D-galactopyranosid)-uronate, more particularly the methyl (steroid-Zl-yl tri-O-acetyl-/3-D-galactopyranosid)-uronate, which is then reacted with an alkaline hydrolyzing agent, thereby forming the corresponding salt of the steroid 2l-galacturonide.

3,206,359 Patented Sept. 14, 1965 These reactions may be chemically represented as follows:

In the foregoing formulas, Y stands for acyl, R represents alkyl, M stands for cation, ZCH OH stands for a Ring A unsaturated 11,17-bis-oxygenated-20-keto-steroid of the anti-inflammatory pregnane series, and ZCH has the significance above-defined. The salt of the steroid galacturonide may be converted to the steroid galacuronide free acid by reaction with a cation exchange resin on the hydrogen cycle, although the resulting product is unstable under acidic conditions.

Our preferred Ring A unsaturated 11,17-bis-oxygenated 20-keto-2l-hydroxy-steroid 21-galacturonides of the pregnane series are conveniently prepared by reacting the steroid 21-free alcohol and the alkyl (tri-O-acyl-a-D-galactopyranosyl bromide)-ur'onate together in a hydrocarbon solvent, such as benzene, in the presence of a base such as silver carbonate, and heating the resulting mixture at an elevated temperature. During the course of the reaction, the color of the reaction mixture ordinarily changes from yellow to maroon and, where silver carbonate is used as the base, the silver bromide produced during the reaction forms as a suspension in the reaction mixture. The solution containing the steroid-uronate reaction product is then separated from the silver bromide (or other bromide salt by-products) and the filtered solution is then evaporated to dryness to give the corresponding alkyl (Ring A unsaturated 11,17-bis-oxygenated-20-ketopregnane-2 l-yl tri-O-acyl-fi-D-galactopyranosid -uronate, which is conveniently purified by chormatography on activated alumina using mixtures of benzene and chloroform as the eluting solvents.

The hydrolysis reaction, which is preferably carried out in a nitrogen atmosphere, is conveniently conducted by bringing together in solution in a lower alcohol solvent such as methanol, the alkyl (Ring A unsaturated 11,17- bis-oxygenated-20-keto-pregnane-2l-yl tri-O-acyl fl-D-galactopyranosid)-ur0nate and a metal alkoxide suchas sodium methoxide, stirring the resulting mixture together at room temperature for a period of about one-half to one hour, and then adding to the reaction solution an aqueous alkaline solution, preferably anaqueous solution of barium hydroxide, and stirring the resulting aqueous mixture at room temperature for an additional one-half one hour period. When barium hydroxide is used, the barium salt of the Ring A unsaturated 11,17-bisoxygenated-21-hydroxy-20-keto-pregnane 21-galacturonide precipitates from the aqueous mixture and is conveniently recovered by filtration. This barium salt is converted to another pharmacologically acceptable salt, as for example, an alkali metal salt such as the sodium salt, an ammonium salt, the choline salt, a basic amino acid salt such as the arginine salt, and the like, by dissolving the barium salt in a minimal amount of water and contacting the aqueous solution with a carboxylic-type cation exchange resin on the appropriate metal cycle, for example the sodium cycle. The resulting aqueous solution of the desired alkali metal salt (e. g. the sodium salt) of the Ring A unsaturated 11,17-bis-oxygenated-2l-hydroxy-ZO-ketopregnane 21-galacturonide is then evaporated at low temperature, preferably by freeze-drying, 'to give the alkali metal salt of the Ring A unsaturated 11,17-bis-oxygenated- 2l-hydroxy-20-keto-pregnane 2l-galacturonide in substantially pure form.

1, Alternatively, the hydrolysis reaction is conducted by bringing together, under nitrogen and in solution in an aqueous alcohol, preferably aqueous methanol, the alkyl (Ring A unsaturated 11,l7-bis-oxygenated-ZO-keto-pregnane-2l-yl tri-O-acyl-B-D-galactopyranosicl)-uronate and a metal alkoxide such as sodium meth'oxide, stirring the resulting mixture together at room temperature for a period of about one-half to one hour, during which time the pH changes from above 12 to about 8. It is ordinarily preferred to employ less than the stoichiometric quantity of an alkali metal alkoxide and, particularly, to utilize only one molecular equivalent thereof, whereupon the hydrolysis of the acyl groupings proceeds by ester interchange with the concomitant formation of the methyl acylate which is readily separable from the alkali metal salt of the galacturonide, formed by saponification of the galacturonate ester, by simple evaporation. It is particularly surprising that the reaction proceeds in this way without any appreciable formation of the undesired by-product, the alkali metal acetate. The reaction mixture is filtered, evaporated to a small volume, diluted with ether, and the precipitate which forms is recovered by filtration, washed with ether, and dried to give the corresponding metal salt (e.g. the sodium salt) of the Ring A unsaturated l1,17-bis-oxygenated-2l-hydroxy-20-ketopregnane 21-galacturonide.

In accordance with these procedures, there are obtained pharmacologically acceptable derivatives, in particular salts with alkali and alkaline earth metals, choline, basic amino acids, and the like, of Ring A unsaturated 11,17- bis-oxygenated-21-hydroxy-ZO-keto-pregnane galacturonides as, for example, the galacturonides of the following Ring A unsaturated 1l,l7-bis-oxygenated-21-hydroxy-20- keto-steroids of the anti-inflammatory pregnane series: cortisone, hydrocortisone, and A -isomers thereof; prednisone and prednisolone; A and/or l6-hydroxy derivatives (including acetonides) of any of the foregoing; derivatives of any of these compounds having fluoro, chloro, or bromo substituents attached to the 6, 9, 12 and/or 16-carbon atoms, and/ or methyl substituents atached to the 2, 6, 12, 15 and/or 16 carbon atoms; and the like. Of particular interest are the sodium salts of the 2l-galacturonides of 6,16-dimethyl-cortisone, 6,16-dimethylhydrocortisone, and their A derivatives; and [3,2-c] pyrazolo derivatives thereof.

The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given for purposes of illustration and not of limitation.

Example 1 To a substantially anhydrous mixture of about 0.015 mole of the Ring A illustrated 11,17-bis-oxygenated-20- keto-pregnane 21-free alcohol, approximately 0.03 mole (about 7.40 g.) of silver carbonate and about 350 ml. of benzene, in a distillation equipment provided with an agitator and protected from moisture, is added a substantially anyhdrous solution of approximately 0.02 mole (about 8.00 g.) of methyl (tri-O-acetyl-a-D-galactopyranosyl bromide)-uronate in ml. of benzene over a period of one hour while distilling benzene from the reaction mixture at a substantially equal rate. During the course of the reaction, the color of the mixture changes from yellow to maroon. The distillation of the benzene is continued for an additional forty minute period, the reaction mixture is cooled to room temperature, and the silver bromide formed during the reaction is separated from the mixture by filtration. The filtered solution is evaporated to dryness in'vacuo to give the corresponding methyl (Ring A unsaturated ,ll,l7-bis-oxygenated-20-keto-pregnane-21-yl tri-O-acetyl-B-D-galactopyranosid)-uronate in a yield approaching that theoretically obtainable.

This material is conveniently purified by dissolving it in benzene-chloroform (9:1), passing the resulting solution through a column containing approximately 350 g. of neutral activated alumina, and eluting the resulting adsorbate, first with 800 ml. of benzene-chloroform (9:1), then with 800 ml. of benzene-chloroform (4:1) (which solvents do not remove appreciable steroidal product from the column) and finally with 4.5 liters of benzenechloroform (7:3). Evaporation of the latter eluate gives the methyl (Ring A unsaturated 11,17-bis-oxygenated-20- keto-pregnane-Zl-yl tri-O-acetyl-fi-D glactopyranosid)- uronate in substantially pure form in a yield over 50% of theory.

In accordance with the above procedure, but using 0.02 mole of ethyl (tri-O-acetyl-u-D-galactopyranosyl brornide)-uronate instead of methyl (tri-O-acetyl-a-D-galactopyranosyl bromide)-uronate, there is obtained the corresponding ethyl) Ring A unsaturate 11,17-bis-oxygenated ZO-keto-pregnane-Zl-yl tri-O-acetyl-B-D-galactopyranosid)-uronate.

Similarly, using 0.02 .mole of another alkyl (tri-O-alkanoyl-a-D-glactopyranosyl bromide)-uronate, as for example butyl (tri-O-propionyl-a-Dgalactopyranosyl bromide)-uronate in the foregoing reaction, there is obtained the corresponding alkyl (Ring A unsaturated 11,17-bisoxygenated 20-keto-pregnane-2Lyl tri-O-alkanoyl-B-D- galactopyranosid)-uronate, as for example butyl (Ring A unsaturated 1l,l7-bis-oxygenated-20-keto-pregnane-21- yl tri-O-propionyl [3 D galactopyranosid) uronate. Where the Ring A unsaturated 11,17-bis-oxygenated-20- keto-pregnane 2l-free alcohol, reacted with silver carbonate and methyl (tri-O-acetyl-u-D-galactopyransoyl bromide)-uronate in accordance with the foregoing procedure, is hydrocortisone, the product obtained is methyl (ll5,17u-dihydroxy-4-pregnene-3,20-dione-2l-yl tri O- acetyl-fi-D-galactopyranosid)-uronate. Similarly, when prednisolone is used as the Ring A unsaturated 11,17-bisoxygenated-ZO-keto-pregnane-Zl-free alcohol, there is obtained methyl (1lfl,l7a-dihydroxy-1,4,-pregnadine-3,20- dione-Zl-yl trio-O-acetyl-fl-D-galactopyranosid)-uronate; x 243 m 13% 197. Similarly, when l6ot-methyl hydrocortisone is used as the Ring A unsaturated 11,17-bisoxygenated-20-keto-pregnane 21-free alcohol, there is obtained methyl (16a-methyl-llfl,17ot-dihydroxy-4-preg nene-3,20-dione-2l-yl tri-O-acetyl-fl-D-galactopyranosid)- uronate; x 240 Ill/L; E% approximately 200.

Utilizing the foregoing procedure, and as reactants, the particular Ring A unsaturated 11,17-bis-oxygenated-20- keto-pregnane 21-free alcohol and alkyl (tri-O-acyl-a-D galactopyranosyl bromide)-uronate indicated in columns 2 and 3 of the following table, there is obtained the corresponding alkyl (Ring A unsaturated 11,17-bis-oxygemated-ZO-keto pregnane-Zl-yl tri-O-acyl-B-D-galactopy ranosid)-uronate shown in column 4 thereof:

keto-pregnane 21-galacturonide is dissolved in a minimum quantity of water at room temperature, and the result- Alkyl (Ring A unsaturated 11,1Z-bis-oxy- Expt. No Ring A unsaturated 11,17-bisoxygenated- Alkyl (tfi-O-acyl-a-D-galactopyranosyl brogenated-20-keto-pregnane-2l-yl tri-O-aeyl- ZO-keto-pregnane 21-free alcohol mide)-uronate fl-D-galactopyranosid)-uronate 1 lfioemethyl prednisolone Methyl (tri-O-acetyl-a-D-galactopyranosyl Methyl (Mia-methyl 1113,17a-dil1ydroxy-L4- bromide)-uronate. pregnacl1ene-3,20-d1one-21-yl tri-O-acetyl- B-D-galaetopyranosid)-uronate.

2 lfiflqnethy] pflniemnm d Methyl (lfifi-rnethyl-llfl,17a-dihydroxy-1,4- pregnadiene-3,20-dione-2l-yl tri-O-aeetyl- B-D-galaetopyranosid)-ur0nate.

3 9a-fluoro-16a-methylpredni nlnn rin Methyl (Qa-fiuoro-lfia-methyl-l16,170,-

dihydroxy-l,4-pregnadiene-3,ZO-dione- 21-y1 tri-O-acetyl-,8-D-galactopyranosid)- uronate.

5 fi -methylprednisolone Ethyl (tri-O-propionyl-a-D-galaetopyran0- Ethyl (fia-methyl-llfi.17a-d1hydroxy-L4- syl br mid mnate, pregnadiene-3,20-dione-2l-yl tri-O-propionyl-fi-D-galactopyranosid)-uronate.

6 fi fluoro prednimlnnp d0 Ethyl (Ga-flHOlO-llfi,l7a-(lihyd10Xy-l,4-

pregnadiene-3,20-dione-21-yl tri-O-propionyl-fl-D-galaetopyranosid)-uronate.

7 6a,16a-(lll11etl1yl prednisolone Methyl (tri-O-acetyl-a-D-ga1actopyranosyl Methyl (6H,](Bu-(limethyl-IIBJ7a-dihy.

bromide)-uronate. droxy-lA-pregnadrened,20%iione-2l-yl tri-O-acetyl-B-D-galaotopyr2m0sid)- uronate.

- pregnatriene-3,20-dione. 1,4,G-pregnatriene-JS,20-d10ne-2Lyl tri-0- acetyl-fl-D-galactopyranosid)-uronate.

9 QQ-flllOlO-lfia-hydlOXY-DldDlSOlOHQ d0 M y q J 7 hy roxyl,4-pregnad1ene-3,20-dione-21-yl tri-O- acetyl-fl-D-galactopyranosid)-uronate.

hydroxy-l,4,6-pregnatriene-3,20-dione. bromide)-uronate. dihydroxy-l,4,6-pregnatriene-3,20-dione- 21-yl ttn-O-benzoyl-fi-D-galaetopyranosid)- urona e. 11 17a,21-dihydroxy-1-allopregnene-3,11,20- Propyl (tri-O-butyryl-a-D-ga1actopyrano- Propyl (l7a-hydr0xy-1-allopregnone-3}11,20-

tri syl bromide)-uronate. trione-2l-yl tr1O-butyryl-fi-D-galactopyranosid)-uronate. 12 9a-fluoro-11fl,1701,21-trihydroxy-1-pregnene- Methyl (tri-O-aeetyl-a-D-galactopyranosyl Methyl (QR-fillOfO-l1B,17a-dlhydrOXy-l- 3,20.di bromide)-uronate. pregnene-3,20-dione-21-yl tri-O-aoetylfl-D-galactopyra.nosid)-uror1ate.

13 l1B,17a,21-trihydroxy-[3,2-o]pyrazolo-4- do Methyl (11B,17a-d1hydroxy-[3,2-e]pyrazolopreg-nene--one. 4-pregnene-20-or1e-21-yl tri-O-aeetyl-B-D- galactopyranosid)-uronate.

pyr3z 10-4 pregnene-2O 0]1e, pyrazol0-4-pregnene-20-one-21-yl tri-O- acetyl-B-Dgalactopyranosid)-uronate.

[3,2-0]pyrazolo-4-pregnene-20-0ne. r xy-[3, -0]pyr z 10-4-pregnene-20-one- 21-yl tri-O-acetyl-/3-D-galaetopyranosid)- uronate.

16 lfia-methyl llfl,17a,21-trihydroxy-[3,2-c]- do Methyl (lfia-methyl-IIBJ7a,dihydroxy- 17 o m dn Methyl (17a-hydroxy-4-pregnene-3,11,20-

trrone-Ql-yl tri-O-aeetyl-B-D-galactopyranosid)-uronate.

18 6,lfia-dimethyl-llfl,17a,21-trihydroxydo Methyl (6,lfia-dimethyl116,17a-dihydroxy)- [3,2-c]pyrazolo-4,6-pregnadiene-20-one. [3,2-0]pyrazol0-4,6-pregnadiene-20-one-21-yl,

tri-O-acetyl-fl-D-galactopyranosid)-uronate 19 6,16a-dimethyl-llfl,17a-21-trihydroxy-2- do Methyl (6,16adimethyl-llfi,17a-dihydroxy)- phenyl-[3,2-c]pyrazole-4,6-pregnad1ene- 2-phenyl-[3,2-0]pyrazolo-4,6-pregnadiene- 20-0ne. 20-0ne-21-yl tri-O-aeetyl-/3-D-galaetopyranosid)-uronate. 20 6,1fia-dimethyl-llfl,17a,21-trihydroxy-4,6- ""1 Methyl (6,16a-dimethyl-11B,l7a-dihydroxypregnadiene-B,20-dione. 4,G-pregnadiene-S,20-dione-2l-yl tri-O- aeetyl-fl-D-galaetopyranosid)-uronate.

Example 2 Approximately 0.005 mole of alkyl (Ring A unsaturated 11,17-bis-oxygenated-ZO-keto-pregnane-Zl-yl tri-O- acyl-fi-D-galactopyranosid)-uronate is dissolved in about 70 ml. of methanol, and to this solution is added about 20 ml. of an approximately 1 N solution of sodium methoxide in methanol. The resulting mixture is stirred under nitrogen at room temperature for approximately minutes. To the resulting mixture is then added, dropwise with stirring, about 250 ml. of an approximately 0.1 N aqueous solution of barium hydroxide, whereupon a precipitate separates. The resulting slurry is stirred at room temperature for an additional period of about 30 minutes, and the precipitated material is recovered by filtration, Washed with methanol until neutral, and dried to give approximately 0.001 mole of the barium salt of the Ring A unsaturated 11,l7-bis-0xygenated-2l-hydroxy- 20-keto-pregnane-2l-galacturonide. Additional material is recovered by cooling the mother liquor and allowing it to stand at 0 C. 7

Approximately 0.001 mole of the barium salt of the Ring A unsaturated ll,17-bis-oxygenated-2l-hydroxy-ZO- ing solution is filtered. To this filtered solution is added about 30 g. of a carboxylic type cation exchange resin (e.g. Amberlite IRC-SO resin manufactured by Rohm & Haas Company, Philadelphia, Pennsylvania) on the sodium cycle, and the mixture is stirred at room temperature for about thirty minutes. The reaction solution is separated from the resin (as by filtration or decantation), extracted with a halogenated hydrocarbon solvent such as methylene chloride (thereby extracting Ring A unsaturated 1 1, l7-bis-oxygenated-2 1-hydr0xy-ZO-ketO-pregnane which may be present), and evaporated to dryness at low temperature (e.g. by freeze-drying) to give approximately 0.001 mole of the sodium salt of the Ring A unsaturated 11,l7-bis-oxygenated-2l-hydroxy-20 keto pregnane-2 l-galacturonide.

In accordance with the above procedure, but using the carboxylic cation exchange resin on another metal cation cycle, for example an alkali metal cation such as potassium (K+), an alkaline earth metal cation such as calcium (Ca++), and the like (instead of the sodium cycle),

there is obtained the corresponding metal salt of the Ring r A unsaturated-11,l7-bis-oxygenated-2l-hydroxy-ZO-ketopregnane 21-galacturonide, such as the potassium salt of the Ring A unsaturated-11,17-bis-oxygenated-2l-hydroxy- 8 hydroxy-ZO-keto-pregnane-2l-galacturonide shown in column 3:

Expt. N0.

Alkyl (Ring A unsaturated-11,17-bis-oxygenated-ZO-keto-pregnane-2l-yl tri-O-aeyl-fl-Dgalactopyranosid)-uronate Ring A unsaturated-11,17-bis-oxygenated-21-hydroxy-20-ketopregnane 21-galacturonide sodium salt uronate.

Methyl (6,lfia-dimethyl-l1,8,17a-dihydroxy-2-phenyl-[3,24]

pyrazolo-l,fi-pregnadiene-20-0ne-2l-yl tri-O-acetyl-dDgalae topyranosid)-uronate.

Methyl (6,lfia-dimethyl-l1B,17adlhydroxy-4,6-pregnadione-3,20-

1fia-methyl-llfi,17u,21-trihydroxy-1,4-pregnadiene-3,20-dione 21- galaoturonide sodium salt lfifi-methyl-llfl,17a,21trihydroxy-l,4-pregnadiene-3,20-dione 21- galacturonide sodium salt fia-fiuoro-ltia-methyl-l1B,17a,21 trihydr0xy-1,4-pregnadiene-3,20-

dione-21-galacturonide sodium salt.

gm-fluoro-lfifi-methyl'llfi,17a,21-trihydroxy-1,4-pregnadiene-3,20-

dione 21-galacturonide sodium salt.

fia-methyl-llfl,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione 21- galaeturonide sodium salt. fia-fluoro-llfi,17,21-trihydroxy-1,4-pregnadienc'3,20-dione 21- galaeturonide sodium salt. 6,lfia-dimethyl-IIB,17a-21-trihydr0xy-1,4-pregnadiene-3,20-dione 3,20-dine 21-galacturonide sodium salt. 6,loa-dimethyl-llfi,17a,21-trihydroxy-1,4,6-pregnatriene-3,20-

dione 21-galactur0nide sodium salt. 9a-fluoro-11B,16m,17a,21-tetrahydroxy-1,4-pregnadiene-3,20-dione 21-galacturonlde sodium salt. Qa-fiuoro-G,16a-dimethyl-11B,17a,21-trihydroxy-1,4,6-preg-natriene- 3,20-dione 21-galacturonide sodium salt.

17a,2l-dihydroxy-l-allopregnene-Zi,11,20-trione 21-galacturonide sodium salt. 9a-fluoro-11B,17a,21-trihydroxy-1-pregnene-3,20-dione 21-galacturonide sodium salt. 11B,17a,21-trihydr0xy-[3,2-c]pyrazolo-4-pregnene-20-one 21-galaeturonide sodium salt. Qa-fluoro-l1B,17a,21-trihydroxy-[3,2-c] pyrazolo-4-pregnene-20- one 21-galaeturonide sodium salt. 9a-fiuoro-16a-methyl-l1B,17a,21-trihydroxy-[3,2-c1pyrazolo-4- pregnane-pm 21-galacturom'de sodium salt.

16a-methyl-11B,17a,21-trihydroxy-[3,2-c] pyrazolo-A-pregnene-20- one 21 -galaeturonide sodium salt.

17a,21-d1hydroxy-4-pregnene-3,11,20-trione 21-galacturonide sodium salt.

6,16 a-dimethyl-11fi,17a,21-trihydroxy-[3,2-c]pyrazolo-4,6-pregnad1e11e-20-one 21-galacturonide sodium salt.

6,lfia-dimethyl-llfl,17a,21-trihydroxy-2-phenyl-[3,2-e1pyrazolo- 4,6-pregnadiene-20-one 21-galacturonide sodium salt.

6,lfia-dimethyl-llB,l7a,21-trihydroxy-4,6-pregnadiene-3,20-dione di0ne-21-y1 tri-O-acetyl-B-D-galaetopyranosid)-uronate.

21-galaeturonide sodium salt.

20-keto-pregnane 21-galacturonide, the calcium salt of the Ring A unsatured-l1,17-bis-oxygenated-2l-hydroxy- 20-keto-pregnane 21-galacturonide, and the like.

In accordance with the above procedure, but using methyl (Ring A unsaturated-11,17-bis-oxygenated-20- keto-pregnane-Zl-yl tri-O-acetyl-fl-D galactopyranosid)- uronate as starting material and the carboxylic cation exchange resin on the sodium cycle, there is obtained the sodium salt of the corresponding Ring A unsaturated- 11,17-bis-oxygenated-2l-hydroxy-ZO-keto pregnane 21- galacturonide.

Where the starting material utilized in the foregoing procedure is methyl (11B,17a-dihydroxy-4-pregnene-3,20- dione-21-yl tri-O-acetyl-B-D-galactopyranosid) uronate and the carboxylic cation exchange resin is used on the sodium cycle, the product obtained is the sodium salt of 11/3,17,21-trihydroxy-4-pregnene-3,20-dione 21 galacturonide. Similarly, when the alkyl (Ring A unsaturated-1 1, 17-bis-oxygenated-20-keto-pregnane-2l-yl tri-O-acyl-B-D- galactopyranosid)-uronate used as starting material in the foregoing procedure is methyl (11fl,17a-dihydroxy-1,4- pregnadiene-3,20-dione-2l-yl tri-O-acetyl-fl D galactopyranosid)-uronate and the carboxylic cation exchange resin is used on the sodium cycle, there is obtained the sodium salt of 11fl,7a,21-trihydroxy-1,4-pregnadiene-3,20- dione 21-galacturonide A 246 m E% 167. Similarly, when methyl (16a-methyl-11fi,17ot-dihydroxy-4-pregnene-3,20-dione-21-yl tri-O-acetyl-fl-D-galactopyranosid)- uronate is used as starting material and the carboxylic cation exchange resin is used on the sodium cycle, there is obtained the sodium salt of l6ot-methyl-llfi,l7a,2ltrihydroxy-4-pregnene-3,20-dione 21-galacturonide.

Utilizing the foregoing procedure, and as starting material, the particular alkyl (Ring A unsaturated-11,17-bisoxygenated-20-keto-pregnane-2l-yl tri-O-acyl-B-D galactopyranosid)-uronate indicated in column 2 of the following table, there is obtained the sodium salt of the corresponding Ring A unsaturated-l1-,17-bis-oxygenated-21- Example 3 of methanolIa'nd to this solution is added about 1.5 ml.

water and about 2.5 ml. of an approximtely 2.4 N methanolic sodium methoxide solution. The color of the reaction solution immediately changes from yellow to orange. The reaction solution is then stirred at room temperature under a nitrogen atmosphere for a period of approximately 30 minutes. The pH of the solution changes from above 12 to approximately 8. The reaction mixture is filtered, evaporated in vacuo to slightly less than /2 the original volume (about 20 ml.). Diethyl ether is added, whereupon a precipitate forms, and the addition of the ether is continued until no further precipitation occurs. The precipitated material is recovered, washed with ether, and dried to give the sodium salt of the Ring A unsaturated 11,17-bis-oxygenated-2l-hydroxy- 20-keto-pregnane 21-galacturonide in a yield of approximately of that theoretically obtainable.

In accordance with the above procedure, but using an aqueous methanolic solution containing another alkali metal alkoxide, such as potassium ethoxide (instead of the sodium methoxide), there is obtained the corresponding alkali metal salt of the Ring A unsaturated 11,17-bis-oxygenated-Zl-hydroXy-20-keto-pregnane 21 galacturonide, such as the potassium salt of the Ring A unsaturated 11,17 bis-oxygenated-Z1-hydroXy-20-keto-pregnane 21- galacturonide, and the like.

In accordance with the above procedure but using methyl (Ring A unsaturated 11,17-bis-oxygenated-20-ketopregnane 21 yl tri O acetyl-B-D-galactopyranosid)- uronate as the alkyl (Ring A unsaturated 11,17-bis-oxygenated 20 keto-pregnane-Zl-yl tri-O-acyl-B-D-galactopyranosid)-uronate and a methanolic solution of sodium methoxide, as the reactants, there is obtained the sodium Where the starting material reacted with the aqueous methanolic solution of sodium methoxide in the foregoing procedure is methyl 11,8,l7u-dihydroxy-4-pregnene- 3,20 dione 21 yl tri-O-acetyl-B-D-galacto-pyranosid)- uronate, the product obtained is the sodium salt of 115, 170:,21 tri-hydroxy 4 pregnene-3,20-dione 21-galacturonide. Similarly, when the alkyl (Ring A unsaturated 1 1,17-bis-oxygenated-20-keto-pregnane-2l-yl tri-O-acyl-p- D-galactopyranosid)-uronate, used as starting material in the foregoing reaction with sodium methoxide in aqueous methanol, is methyl (115,17a-dihydroxy-1,4-pregnadiene- 3,20 dione 21-yl tri-O-acetyl-B-D-galactopyranosid)uronate, there is obtained the sodium salt of 11/3,17a,21-trihydroXy 1,4 pregnadiene-3,20-dione 2l-galacturonide. Similarly, when methyl (16a-methyl-11fl,17a-dihydroxy- 4-pregnene 3,20 dione-Zl-yl tri-O-acetyl-fi-D-galactopyranosid)-uronate is used as starting material in the foregoing reaction with sodium methoxide in aqueous methanol, there is obtained the sodium salt of 16u-methyl- 11[3,17a,21-trihydroxy-4-pregnene-3,20-dione 21-galacturonide.

The alkyl (tri-O-acyl-u-Dgalactopyranosyl bromide)- uronates such as methyl (tri-O-acetyl-u-D-galactopyranosyl bromide)-uronate, used as starting materials in the foregoing examples are prepared as follows: a mixture of about 18 g. of galacturonolactone, 0.15 g. of sodium methoxide and 100 ml. of methanol is stirred at room temperature for a period of approximately 1 hour. The resulting reaction solution is evaporated to a vast syrup in vacuo. This syrup is then dissolved in approximately 70 ml. of acetic anhydride, and to this solution is added, dropwise with stirring, a solution of 0.3 ml. of perchloric acid in ml. of acetic anhydride, while maintaining the reaction temperature below about 40 C. The resulting mixture is allowed to stand at room temperature for a period of about hours, an additional 0.1 ml. of perchloric acid is added, and the resulting solution cooled to about 0 C. and maintained at that temperature for an additional 15-hour period. The crystalline material which separates is recoveredby filtration, washed with ether, and recrystallized from ethanol to give substantially pure methyl tetra-O-acetyl-fl-D-galactopyranuronate.

Utilizing the foregoing procedure but using, (1) in place of the 100 ml. of methanol there employed, approximately 100 m1. of another alcohol such as ethanol, propanol, butanol, benzyl alcohol, and the like, (2) in place of the 0.15 g. of sodium methoxide, about 0.15-0.2 g. of a sodium alkoxide corresponding to the alcohol utilized, i.e. sodium ethoxide, sodium propoxide, sodium butoxide, sodium benzoxide, respectively, and (3) in place of the 70 ml. of acetic anhydride, about 70100 ml. of another acyl anhydride such as propionic anhydride, butyric anhydride, and the like, there is obtained the corresponding alkyl tetra-O-acyl-/3-D-galactopyranuronate such as ethyl tetra-O-propionyl-B-D-galactopyranuronate; butyl tetra-O- butyryl-fi-D-galactopyranuronate; benzyl tetra-O-acetyl-B- D-galactopyranuronate, and the like.

A solution of about 50 g. of methyl tetra-O-acetyl-B- D-galactopyranuronate in about 200 ml. of 30% hydrobromic acid in acetic acid is cooled to about 0 C. and allowed to stand at that temperature for a period of about 15 hours. The solvent is evaporated from the reaction solution in vacuo at a temperature of below about 40 C., and the residual material is dissolved in 100 ml. of chloroform. The chloroform solution is washed with cold saturated sodium bicarbonate solution, then with water, and dried over anhydrous sodium sulfate. The washed dried cholorform solution is evaporated in vacuo to a syrup. The residual syrup is dissolved in about 150 ml. of absolute ethanol, treated with activated charcoal, filtered, and the filtered solution cooled to about 0 C. and allowed to stand at that temperature for about 15 hours. The crystalline material which separates is recovered by filtration and dried to give substantially pure methyl (tri-O-acetyla-D-galactopyranosyl bromide) -uronate.

Similarly, utilizing other alkyl tetra-O-acyl-fl-D-galactopyranuronates such as ethyl tetra-O-propionyl-fl-D-galactopyranuronate; butyl tetra-O-butyryl-B-Dgalactopyranuronate; benzyl tetra-O-acetyl-fl-D-galactopyranuronate, and the like in the foregoing reaction with the 30% hydrobromic acid in acetic acid, there is obtained the corresponding alkyl (tri-O-acyl-a-Dgalactopyranosyl bromide)- uronate such as ethyl (tri-O-propionyl-a-D-galactopyranosyl bromide)-uronate; butyl (tri-O-butyryl-a-D-galactopyranosyl bromide)-uronate; benzyl (tri-O-acetyl-a-D galactopyranosyl bromide)-uronate, and the like.

These new Ring A unsaturated 11,17-bis-oxygenated- ZO-keto-steroid galacturonides of the anti-inflammatory pregnane series possess anti-inflammatory activity characteristic of cortisone, and their use results in little salt and water retention or adrenal atrophy. They are, in addition, remarkably free from thymus involution and bodyweight-loss side effects ordinarily accompanying the prolonged administration of anti-inflammatory steroids. They are normally administered in a daily maintenance dosage range comparable with that utilized in the administration of the corresponding Ring A unsaturated 11,17-bis-oxygenated ZO-keto-steroid, e.g. from about 25 to mg. per day for cortisone galacturonides or hydrocortisone galacturonides; about 2.5 and 10 mg. per day for prednisolone galacturonide; and about 0.25 to 5 mg. per day in the case of dexamethasone galacturonide, although, in view of their selective anti-inflammatory action (substantially unaccompanied by undesired side effects) they may, in the'case of aggravated inflammatory conditions, be administered in substantially higher dosages without attendant risk of side effects; and, in milder conditions, may often be administered in substantially lower dosages in view of their pronounced anti-inflammatory action directly at the site of the inflammation. While, due to their relative instability in acid solution, these Ring A unsaturated 11,17-bis-oxygenated 20-keto-steroid galacturonides are ordinarily administered by injection, they may also be administered by the oral route, preferably admixed with, and/ or coated by, an alkaline-reacting pharmacologically-acceptable bulfer substance, or in an enteric-coated capsule.

The Ring A unsaturated 11,17-bis-oxygenated-l6-meth- 'yI-ZO-keto-pregnane 2l-free alcohols, more particularly the 16aand .l6 3-methyl derivatives of cortisone and hydrocortisone, their A derivates, 6-methyl an-d 6rnet-hyl-A derivatives of the foregoing, and [3,2-c] pyrazolo-an-alogues thereof, used as starting materials in the foregoing examples, are prepared in accordance with the following procedures:

A solution of 10.22 g. of methyl iodide in 50 ml. of ether is added to 1.73 g. of magnesium in 50 ml. of ether. To the resulting etheral solution of methyl magnesium iodide, maintained under a nitrogen atmosphere, is added 0.045 g. of anhydrous cuprous chloride. To this mixture is added, over a period of about one hour, during which period the reaction mixture is stirred vigorously and maintained at approximately room temperature, a solution of about 5.6 g. of 3a-acet0xy-l6-pregnane-11,20-dione in 175 ml. of ether. A white granular solid separates during this addition. The resulting mixture is heated under gentle reflux for two hours after which the reaction mixture is cooled, and ml. of saturated, aqueous ammonium chloride solution is added followed by 200 ml. of ether. The layers are separated, and the etheral layer is washed with three 50 ml. portions of water. The washed etheral layer is dried, and the solvent evaporated in vacuo to give a brown viscous oil. The latter material is heated for 15 minutes at 6070 C. with a mixture of 25 ml. acetic anhydride and 25 ml. pyridine and the acetylated product is purified by chromatography on acid-washed alumina followed by crystallization from petroleum ether to give approximately 1.5 g. of substantially pure 3oc-acetoxy-l6a-methyl-pregnane-11,20-dione.

To a solution of 0.8 g. of 3u-acetoxy-16a-methyl-pregnane-ll,20-dione in 40 ml. of methanol is added 1.5 ml. of concentrated aqueous hydrochloric acid and the resulting solution is stirred overnight at about 25 C. The reaction solution is evaporated in vacuo at 25 C. to a small volume, and the concentrated solution is poured into 50 ml. of ice water. The white solid which precipitates is recovered by filtration, washed with water and recrystallized from ethyl acetate to give 3a-hydroxy-16a-methylpregnane-l 1,20-dione.

A solution of 22 g. of 3ot-acetoxy-l6ot-methyl-pregnane- 11,20-dione and 1 g. of p-toluene-sulfonic acid in 250 ml. of acetic anhydride is heated at reflux under nitrogen for a period of approximately 3 days. Two grams of potassium acetate (anhydrous) is added, and the volatile solvents are separated by distillation in vacuo. The residual material is extracted with benzene, and the benzene extract is filtered to remove insoluble material. The benzene extracts are evaporated to a volume of 100 ml. and petroleum ether is added to the cloud point. The resulting solution is adsorbed on 660 g. of acid-washed alumina; the. alumina adsorbate is then washed with 2 liters of petroleum ether. The adsorbate is then eluted with 85:15 petroleum ether-ether mixture, and the first four liters of eluate is collected, and evaporated to dryness in vacuo to give a mixture of enol acetates containing 301,20 diacetoxy 16a methyl-17 (20)-pregnene-l l-one. This mixture of enolates, weighing approximately 14 g., is dissolved in 50 ml. of benzene and treated with an excess of per-benzoic acid over a 16-hour period. The reaction mixture is shaken with dilute aqueous potassium hydroxide solution until the benzene layer is free of per-benzoic acid; the benzene layer is then washed with water until neutral, dried, and the solvent evaporated in vacuo to give a crystalline material, 17a,20-epoxy-3u,20- diacetoxy-16ot-methyl-pregnane-1l-one. The latter material is dissolved, without purification, in 200 ml. of methanol, 120 ml. of water and 10 g. of potassium bicarbonate, and the resulting solution is heated at reflux under nitrogen for a period of 16 hours. The methanol is evaporated from the hydrolysis solution in vacuo, and the residual oil is extracted from the resulting aqueous solution with chloroform. The chloroform extract is washed with water to neutrality, dried, and the chloroform is evaporated under reduced pressure. The residual oil is triturated with ether, and the crystalline material thus formed is recrystallized from ethyl acetate-petroleum ether to give 3a,Not-dihydroxy-l6ot-methylpregnane- 11,20-dione. 7

To a solution of 7.0 g. of 3a,Nix-dihydroxy-Mot-methyl- 'pregnane-11,2 -dione in 50 ml. of chloroform is added dropwise with stirring a solution containing 3.36 g. of bromine in 24.2. ml. of chloroform over a period of about 60 minutes. The reaction mixture is dissolved in 200 ml. of ethyl acetate, and the resulting solution washed with water until neutral, dried, and the solvents evaporated therefrom in vacuo. The residual crude material is dissolved in a minimum quantity of ethyl acetate, the resulting solution is diluted with ether, and the mixture is stirred until crystals form. The crystalline product is recovered by filtration and washed, by slurrying, with 50:50 ether-petroleum ether mixture to give about 5 g. of 21 bromo 3ot,17a dihydroxy-l6a-methyl-pregnane 11,20-dione.

This 5 g. of 21-bromo-3oc,Nix-dihydroxy-16ix-methylpregnane-1l,20-dione is mixed with 5.0 g. of anhydrous potassium acetate, 4.0 g. of sodium iodide and 0.03 ml. of glacial acetic acid, and 100 ml. of acetone is added to the resulting mixture. This mixture is then heated at reflux, with stirring, for a period of about 16 hours, and the reaction mixture is cooled, filtered, and the insoluble material is washed with acetone. The filtered solution is evaporated in vacuo thereby removing the solvents, and the residual material is slurried with water, and the aqueous mixture extracted with ethyl acetate. The ethyl acetate extract is washed with water to neutrality, dried, and the solvent is evaporated in vacuo to give an oil. This oil is crystallized from ether, and recrystallized from ethyl acetate-ether to give 3a,17a,21-trihydroxy-16otmethyl-pregnane-l 1,20-dione 2 l-acetate.

A solution of 400 mg. of 3a,l7oc,21-lZIihydI0Xy-l6w methyl-pregnane-l1,20-dione 21-acetate in 4 ml. of pyridine is added to the complex formed by the addition of 400 mg. of chromium trioxide to 4 ml. of pyridine. The mixture is swirled until thoroughly mixed, and then allowed to stand at room temperature overnight. The reaction mixture is poured into water, and the aqueous mixture is extracted with ether, and then twice with ethyl acetate. The combined ether and ethyl acetate extracts are washed with dilute aqueous sulfuric acid at about 0 C., and then with water until neutral. The organic solvent layer is then dried, the solvents are evaporated therefrom in vacuo, and the residual crystalline material is purified by crystallization from ethyl acetate to give 17a,21 dihydroxy l6a-methyl-pregnane-3,11,20-trione 2l-acetate.

To 100 mg. of l7a,2l-dihydroxy-l6u-methyl-pregnane 3,11,20-trione 21-acetate dissolved in 2 ml. of chloroform and 2.25 ml. of glacial acetic acid, at a temperature of C., is added two drops of a 0.001 N solution of dry HBr in glacial acetic acid. To about 0.38 ml. of 0.001 N HBr in glacial acetic acid, at 55 C., is added 0.43 ml. of a solution containing 40 mg. of bromine in chloroform, and the resulting solution is added, over about a l0-minute period, to the solution of the steroid, while maintaining the reaction mixture at about 55 C. The reaction mixture is allowed to stand at 55 C. for about one-half hour; a solution containing 250 mg. of sodium acetate :in 3 ml. of water is added, and the resulting mixture is stirred for about 5 minutes. Five milliliters of water are then added, and the aqueous'mixture is extracted with ethyl acetate. The ethyl acetate extract is washed with aqueous sodium bicarbonaate solution to neutrality, then with Water, dried, and the solvent is evaporated in vacuo. The residual material is dissolved in 2 ml. of acetone, and to the solution is added 25 mg. of sodium bromide and 1 ml. of water. The resulting mixture is heated under reflux for a period of about 5 hours, the reaction mixture is cooled, and the acetone is evaporated in vacuo. The residual material is extracted into ether, the ether extract is washed with water, dried, and the solvent is evaporated to a volume of about 1 ml.; petroleum ether is added to this solution, and the crystalline material which separates is recovered and dried to give approximately 90 mg. of 4-bromo-17-a,2l-dihydroxyl6a-methyl-pregnane-3,l 1,20-trione 2 l-acetate.

A mixture of 48 mg. of semicarbazide, 48 mg. of 4- bromo-17a,2l-dihydroxy 16oz methyl-pregnane-3,ll,20- trione 21-acetate and 0.6 ml. of ethanol is heated under reflux in contact with a nitrogen atmosphere for a period of about three days, and the reaction solution is evaporated to a small volume, diluted with water and the crystalline material recovered and purified by recrystallization from aqueous methanol to give 3,20-bis-semicarbazido-l7a,2ldihydroxy-l6u-methyl-4-pregnene-3,l1,20 trione 2l-acetate. Fifty milligrms of 3,20-bis-semicarbazido-l7a,2l-dihydroxy-l6a-methyl-4-pregnene-3,l 1,20-trione 2 l-acetate is dissolved in a mixture of 1.0 cc. of benzene and 1.0 cc. of 1.1 N methanolic potassium hydroxide, and the solution is allowed to stand at room temperature for a period of about 10 minutes. The solution is then acidified with acetic acid, the benzene is evaporated in vacuo, and the residual material is recrystallized from ethyl acetate to give 3 ,20-bis-semicarbazido- 17o,2 l-dihydroxy-l 6oc-methyl- 4-pregnene-3 ,1 1,20-trione.

A mixture of mg. of 3,20-bis-semicarbazido-l7u,2l-

13 dihydroxy-l6u-methyl-4-pregnene-3,1 1,20-trione, 0.2 ml. of dimethylformamide, 0.6 ml. of chloroform, and 1.5 ml. of 1.0 N aqueous hydrochloric acid is heated under reflux for a period of about three hours. The resulting twophase system is cooled to a temperature of approximately 15 C., and the layers are separated. The aqueous layer is extracted with chloroform, and the chloroform extracts are combined with the original chloroform-dimethylformamide solution. The combined organic layer is washed with an aqueous solution of sodium bicarbonate, and the chloroform and dimethylformamide in the combined organic layer is replaced Wtih ethyl acetate by evaporation in vacuo. Petroleum ether is aded and the resulting solution is subjected to a partition chromatogram using aqueous methanol as the stationary phase and benzene-chloroform as the moving phase to give 17a,21-dihyd'roxy- 1 6a-methyl-4-pregnene-3 ,1 1,20-trione.

A solution of 45 mg. of 3,20-bis-semicarbazido-1701,21- dihydroxy-l6et-methyl-4-pregnene-3,l1,20 trione 21-acetate, 17 mg. of sodium borohydride, 1 ml. of tetrahydrofuran and 0.3 ml. of water is maintained at reflux temperature for approximately one hour. The reaction solution is cooled to about 15 C., and the excess sodium borohydride decomposed by the addition of a solution of 27 mg. of glacial acetic acid in 0.2 ml of water. The tetrahydrofuran is evaporated in vacuo, and the residual material is extracted with ethyl acetate. The ethyl acetate extracts are washed with a saturated salt solution, Water, aqueous sodium bicarbonate solution and again with water. The extracts are dried and the ethyl acetate evaporated in vacuo to give 3,20-bis-semicarbazido-1lfl,17u,21- trihydroxy-16a-methyl-4-pregnene-3,20-dione.

A mixture of 60 mg. of 3,20-bis-semicarbazido- 11B,17a,21 trihydroxy 16a methyl-4-pregnene 3,20-

dione, 0.2 ml. of dimethylformamide, 0.6 ml. of chloroform, and 1.5 ml. of 1.0 N aqueous hydrochloric acid is heated under reflux for a period of about three hours. The resulting two-phase system is cooled to a temperature of approximately 15 C., and the layers are separated. The aqueous layer is extracted with chloroform, and the chloroform extracts are combined with the original chloroform-dimethylformamide solution. The combined organic layer is washed with an aqueous solution of sodium bicarbonate, and the chloroform and dimethylformamide in the combined organic layer is replaced with ethyl acetate by evaporation in vacuo. Petroleum ether is added and the resulting solution is subjected to a partition chromatogram using aqueous methanol as the stationary phase and benzene-chloroform as the moving phase to give 11B,17a',21 trihydroxy 16a methyl 4 pregnene- 3,20-dione. The latter material is reacted with an excess ofacetic anhydride in pyridine at room temperature for a period of about fifteen hours, and the crude acetylated product is recrystallized from ethyl acetate to give 1l'fi,17a,21 trihydroxy 16a methyl 4 pregnene- 3,20-dione 21-acetate.

To a cooled solution of 600 mg. of 11fl,17u,21-trihydroxy-l6a-methyl-4-pregnene-3,20-dione 21-acetate in 5.0 ml. of dry pyridine is added 0.15 ml. of phosphorous oxychloride, and the mixture is allowed to stand at room temperature for a period of approximately 15 hours. The reaction solution is evaporated in vacuo at a temperature of about 20 C. to a volume of 23 ml. Seventeen milliliters of water is added slowly to the concentrated solution, with stirring, and the aqueous mixture is extracted with ethyl acetate. The combined ethyl acetate extracts are washed with water, then with dilute aqueous hydrochloric acid solution, again with water, and then with a dilute aqueous sodium bicarbonate solution. The washed ethyl acetate solution is dried, and the solvent is evaporated in vacuo; the residual material it triturated with ether, and the crystalline material is recrystallized from ethyl acetate-ether to give 17a,21-dihydroxy-16amethyl-4,9(11)-pregnadiene-3,20-dione 21-acetate. A suspension of 330 mg. of 17u,2l-dihydroxy-l6u-methyl- 14 4,9(l1)-pregnadiene:3,20-dione 21-acetate and 1.8 g. of N- bromo-succinimide in a mixture of 50 ml. of dioxane and 10 ml. of water is cooled to 10 C. Then with stirring, 10 ml. of cold 1.0 N aqueous perchloric acid is added. The temperature of the reaction mixture is allowed to rise to 15 C. and is maintained at this point for about two and one-half hours during which time the solid material slowly dissolves. The resulting yellow solution is treated with 1.0 ml. of allyl alcohol to discharge the color and decompose the remaining N-bromo-succinimide, and the resulting solution is evaporated to a small volume in vacuo. The concentrated solution is diluted with water, and the aqueous mixture is extracted with ethyl acetate. The ethyl acetate extracts are washed, dried and evaporated to dryness, and the residual material is crystallized from ethyl acetate-ether to give 9u-bromo-11;8,l7u,2l-trihydroxy-l6u-methyl-4-pregnene-3,20-dione 2l-acetate.

A solution of 210 mg. of 9a-bromo-11B,17a,21-trihydroxy-l6u-methyl-4-pregnene-3,20-dione- 21-acetate and 240 mg. of potassium acetate in 10 ml. of absolute ethanol is heated under reflux for two hours. The reaction mixture is cooled to room temperature, and evaporated in vacuo to a small volume. The concentrated aqueous mixture is extracted with three portions of ethyl acetate, and the combined ethyl acetate extracts are washed with water, dried, evaporated to dryness in vacuo. The residual material is crystallized from ethyl acetate-ether to give 913,115 epoxy 1711,21 dihydroxy 16oz methyl- 4-pregnene-3,20-dione ZI-acetate. To a solution of 83 mg. of anhydrous hydrogen fluoride in 4.7 ml. of ice-cold alcohol-free chloroform is added an ice-cold solution of 416 mg. of 9,8,1lfl-epoxy-17a,21-dihydroxy-1Got-methyl- 4-pregnene-3,20-dione 21-acetate. The solution is mixed thoroughly and maintained at 0 C. for two hours, at the end of which time 13.0 ml. of ice-cold 20% aqueous sodium acetate is added, and the resulting mixture agitated vigorously. The layers are separated, and the chloroform layer is washed with water until free of acid, dried, and the chloroform evaporated in vacuo. The residual material is crystallized from acetone-petroleum ether to give 9a-fluoro-l1fi,17 x,2l-trihydroxy-16a-methyl-4-pregnene-3,20-dione 21-acetate. Fifty milligrams of 9a-fluoro- '11fi',17oc,2l trihydroxy 16oz methyl 4 pregnene 3,20- dione 21-acetate is dissolved in a mixture of 1.0 cc. of 1 N methanolic potassium hydroxide, and the solution is allowed to stand at room temperature for a period of about ten minutes. The solution is then acidified with acetic acid, the benzene is evaporated in vacuo, and the residual material is crystallized from ethyl acetate-ether to give 9a-fluoro-11 3,17a,21-trihydroxy-16a-methyl-4- pregnene-3,20-dione.

A solution of 400 mg. of 9a-fluoro-11B,l7a,21-trihydroxy-l6a-methyl-4-pregnene-3,20 dione 21-acetate in 4 ml. of pyridine is added to the complex formed by the addition of 400 mg. of chromium trioxide to 4 ml. of pyridine. The mixture is swirled until thoroughly mixed and then allowed to stand at room temperature overnight. The reaction mixture is poured into water, and the aqueous mixture is extracted with ether and then twice with ethyl acetate. The combined ether and ethyl acetate extracts are washed with dilute aqueous sulfuric acid at about 0 C., and then with water until neutral. The organic solvent layer is then dried, the solvents are evaporated therefrom in vacuo, and the residual crystalline material is purified by crystallization from ethyl acetate-ether to give 9u-fluoro-l7a,2l-dihydroxy-16a-methyl-4-pregnene- 3,11,20-trione 21-acetate. Fifty milligrams of 9u-fil10l0 1704,21 dihydroxy 16ot-methyl 4 pregnene 3,11,20- trione 21-acetate is dissolved in a mixture of 1.0 cc. of benzene and 1.0 cc. of 1 N methanolic potassium l1ydroxide, and the solution is allowed to stand at room temperature for a period of about ten minutes. The solution is then acidified with acetic acid, the benzene is evaporated in vacuo, and the residual material is crystal- 15 lized from ethyl acetate-ether to give 9ot-fluoro-17ot,21- dihydroxy-l6a-methyl-4-pregnene-3,1 1,20-trione.

To a solution of 110 mg. of 17u,21-dihydroxy-16amethyl-4-pregnene3,l1,20-trione 21-acetate in 6 ml. tbutanol, 0.01 ml. glacial acetic acid and 0.03 ml. of acetic anhydride is added 70 mg. of selenious acid (H SeO The mixture is heated to the boiling point overnight, another 50 mg. of selenious acid is added, and the heating is continued for an additional 24 hours. The solution is decanted from metallic selenium and evaporated to an oil which is then dissolved in ethyl acetate. The ethyl acetate solution is washed with aqueous sodium bicarbonate and then with water until neutral, and dried. The solvent is evaporated from the dried solution to give an oil which is dissolved in benzene and adsorbed from this solvent on acid-washed alumina. The adsorbate is eluted with ether-petroleum ether and then with mixtures of ether and chloroform, increasingly rich in chloroform. The 4:6 ether-chloroform eluates are combined, evaporated to dryness, and the residual material recrystallized from ethyl acetateether to give 17oc,21-dihydroxy- 16oz methyl 1,4 pregnadiene 3,11,20 trione 21- acetate; M.P. 208-212 C. Fifty milligrams of 17a,21- dihydroxy-l6a-methyl-1,4-pregnadiene-3,11,20 trion 21- acetate is dissolved in a mixture of 1.0 cc. of benzene and 1.0 cc. of 1 N methanolic potassium hydroxide, and the solution is allowed to stand at room temperature for a period of about ten minutes. The solution is then acidified with acetic acid, the benzene is evaporated in vacuo, and the residual material is crystallized from ethyl acetateether to give 17a,21-dihydroxy-16a-methyl-1,4-pregnadiene-3 ,11,20-trione.

To a solution of 100 mg. of 11B,17a,21-trihydroxy- 16u-methyl-4-pregnene-3,20-dione 21-acetate in 6 ml.

t-butanol, 0.01 ml. glacial acetic acid and 0.03 ml. of

acetic anhydride is added 70 mg. of selenious acid. The mixture is heated to the boiling point overnight, another 50 mg. of selenious acid is added, and the heating is continued for an additional 24 hours. The solution is decanted from metallic selenium and evaporated to an oil which is then dissolved in ethyl acetate. The ethyl acetate solution is washed with aqueous sodium bicarbonate and then with water until neutral, and dried. The solvent is evaporated from the dried solution to give an oil which is dissolved in benzene and adsorbed from this solvent on acid-washed alumina. The adsorbate is eluted with ether-petroleum ether and then with mixtures of ether and chloroform, increasingly rich in chloroform. The 4:6 ether-chloroform eluates are combined, evaporated to dryness, and the residual material recrystallized from ethyl acetate-ether to give 11fl,17a,21-trihydroxy- 16a-methyl-1,4-pregnadiene-3,20-dione 21 acetate. Fifty milligrams of 11B,17o,2 1. trihydroxy 16a methyl 1,4- pregnadiene-3,20-dione 21-acetate is dissolved in a mixture of 1.0 cc. of benzene and 1.0 cc. of 1 N methanolic potassium hydroxide, and the solution is allowed to stand at room temperature for a period of about ten minutes. The solution is then acidified with acetic acid, the henzene is evaporated in vacuo, and the residual material is crystallized from ethyl acetate-ether to give 11fl,17u,21- trihydroxy-16a-methyl-1,4-pregnadiene-3,20-dione.

To a solution of 110 mg. of 9a-fluoro-17-a,21-dihydroxy 16amethyl-4-pregnene-3,11,20-trione 21-acetate in 6 ml. t-butanol, 0.01 ml. glacial acetic acid and 0.03 ml. of acetic anhydride is added 70 mg. of selenious acid (H SeO The mixture is heated to the boiling point overnight, another 50mg. of selenious acid is added, and the heating is continued for an additional 24 hours. The solution is decanted from metallic selenium and evaporated to an oil which is then dissolved in ethyl acetate. The ethyl acetate solution is washed with aqueous sodium bicarbonate and then with water until neutral, and dried. The solvent is evaporated from the dried solution to give an oil which is dissolved in benzene and adsorbed is eluted with etherpetroleum ether and then with mixtures of ether and chloroform, increasingly rich in chloroform. The 4:6 ether-chloroform eluates are combined, evaporated to dryness, and the residual material recrystallized from ethyl acetate ether to give 90: fluoro 170;,21 dihydroxyl6a-methyl-1,4- pregnadiene 3,11,20 trione 21-acetate. Fifty milligrams of 9a-fluoro 170:,21 dihydroxy 16amethyl-l,4-pregnadiene-3,11,20-trione ZI-acetate is dissolved in a mixture of 1.0 cc. of benzene and 1.0 cc. of 1 N methanolic potassium hydroxide, and the solution is allowed to stand at room temperature for a period of about ten minutes. The solution is then acidified with acetic acid, the benzene is evaporated in vacuo, and the residual material is crystallized from ethyl acetate-ether to give 9a-fluoro-17a,21-dihydroxy-16a-methyl-1,4 pregnadiene- 3,1 1,20-trione.

To a solution of 100 mg. of 9a-fluoro-11[3,17u,21-trihydroxy-l6a-methyl-4-pregnene-3,20-dione ZI-acetate in 6 ml. t-butanol, 0.01 ml. glacial acetic acid and 0.03 ml. of acetic anhydride is added mg. of selenious acid. The mixture is heated to the boiling point overnight, another 50 mg. of selenious acid is added, and the heating is continued for an additional 24 hours. The solution is decanted from metallic selenium and evaporated to an oil which is then dissolved in ethyl acetate. The ethyl acetate solution is washed with aqueous sodium bicarbonate and then with water until neutral, and dried. The solvent is evaporated from the dried solution to give an oil which is dissolved in benzene and adsorbed from this solvent on acid-washed alumina. The adsorbate is eluted with ether-petroleum ether and then with mixtures of ether and chloroform, increasingly rich in chloroform. The 4:6 ether-chloroform eluates are combined, evaporated to dryness, and the residual material recrystallized from ethyl acetate-ether to give 9-a-fluoro-11,8,17a,21-trihydroxy-16amethyl 1,4 pregnadiene 3,20 dione 21-acetate. Fifty milligrams of 9a-fluoro-11/3,17ot,21-trihydroxy-16a-methyl-1,4-pregnadiene-3,ZO-dione ZI-acetate is dissolved in a mixture of 1.0 cc. of benzene and 1.0 cc. of 1 N methanolic potassium hydroxide, and the solution is allowed to stand at room temperature for a period of about ten minutes. The solution is then acidified with acetic acid, the benzene is evaporated in vacuo, and the residual material is crystallized from ethyl acetate-ether to give 9oc-fiUOYO-1l,8,17oc, 21-trihydroxy-16u-methyl-1,4-pregnadiene-3,20-dione.

In a 500 ml. 3-neck flask equipped with condenser, dropping funnel and nitrogen inlet are placed 20 g. of potassium hydroxide in ml. of water, ml. of methanol and 100 ml. of ether. A solution of 10 g. of N-methyl-N-nitroso-tosylamide in 50 ml. of ether is placed in the dropping funnel.

Diazomethane is generated by warming the generation flask to 4045 C. and cautiously adding the N-methyl-N- nitrosotosylamide-ether from the dropping funnel. Nitrogen is utilized to sweep the diazomethane into a solution of 20 g. of 3a-acetoxy 16-pregnene-l1,20-dione 100 ml. of tetrahydrofuran and ml. of ether. The process is continued until the steroid solution remains yellow for several hours. The product, 3a-acetoxy-16u,17a-methyl eneazo-pregnane 11,20-dione largely precipitates from the reaction mixture. After 16 hours, the mixture is filtered, washed with ether and dried in air. Yield about 14 grams, M.P. 186-190 C.

37.4 g. of 3m-acetoxy-16a,17a-methyleneazo-pregnane- 11,20-dione is placed in a 500 ml. round-bottom flask and heated by an oil bath in vacuo (pressure 0.6 mm.). A manometer and 12-liter surge flask are in the line between the reaction flask and pump trap. When the bath temperature reaches 180 C. the 3a-acetoxy-16a,Wot-methyleneazo-pregnane-1l,20-dione begins to melt with evolution of nitrogen. The maximum pressure reached is 83 mm. After 10 minutes at 180l82 C. the melt is cooled. It has xggg 249, 12% 191 and is taken up in about ml. of acetone, filtered through diatomaceous earth, concentrated to about 100 ml., and ether is slowly added to the boiling solution until crystallization occurs. These crystals of 3zxacet0xy-16-methyl- 16-pregnene-11,20-dione weigh about 19.0 g., M.P. 165- 168 C.

A solution of 20.0 g. of 3a-acetoxy-16-methyl-16-pregnene-11,20-dione dissolved in 600 ml. of methanol, is cooled to 18 C., and 80 ml. of 30% hydrogen peroxide followed by 80 ml. of 2.5 N sodium hydroxide are added. Considerable material precipitates from solution, but all redissolves on stirring the reaction mixture at 2530 C. for 40 minutes. The solution is kept at 15-20 C. for 18 hours at which time the ultraviolet maximum at 249 has completely disappeared. Then 600 ml. of saturated salt water is slowly added, the crystalline precipitate is filtered, Washed with water, and dried in air and in vacuum. The 16a,17a-expoxy-3a-hydroxy-16e-methy1-pregnane-11,20-dione thus formed weighs about 17 g.; M.P. 176-177 C., hexagonal prisms M.P. 178-180 C. from acetone-ether.

To a solution of 2.69 g. of 16u,17a-epoxy-3a-hydroxy- 16B-methyl-pregnane-11,20-dione in 55 ml. dioxane is added 27 ml. of 2 M aqueous perchloric acid. The clear solution is kept at 25-30 C. for 65 hours. Cold water (175 ml.) is added, the slurry chilled to 8 C. and filtered after 30 minutes. The precipitate, containing a mixture of 3a,l7a dihydroxy-16-methyl-15-pregnene-11,20-dione and 3 a,17a-dihydroxy-16-methylenepregnane-1 1,20-dione is washed with water, and dried in air and finally at 50 C. in vaccum. Yield: approximately 2 g.; M.P. sintering at about 150 C., melting at 158l67 C. The relative proportion of 3a,17m-dihydroxy-16-methyl-15-pregnene- 11,20-dione and 3a,17u dihydroxy-16-methylene-pregmane-11,20-dione is estimated to be of the order of 1:1.

A solution 3.05 g. (8.47 millimols) of the olefin mixture of 3a,17a-dihydroxy-16-methylene-pregnane-11,20- dione in 80 ml. of methanol is reduced in hydrogen at 1 atmosphere and 25 C. in the presence of 2.0 g. of 25% palladium-calcium carbonate catalyst. Modification of the hydrogen condition-s, pH, solvent, catalyst, etc. alters the isomer ratio significantly. Uptake of the calculated amount of hydrogen is complete in 45 minutes. The mix ture is stirred an additional 30 minutes and filtered through diatomaceous earth. The colorless filtrate is taken to dryness and crystallized from ether; a mixture of 30:,170: dihydroxy-16a-methyl-pregnane-11,20-dione and 3 a,17ocdihydroxy-16B-methyl-pregnane-1 1,20-dione is obtained; weight about 3 g., sintering at 150 C. melting at 166l82 C.

The product consists of 3a,17a-dihydroxy-16a-methylpregnane-11,20-dione and 3a,17ocd.ihydroxy-16fi-methylpregnane-11,20-dione in the ratio ca. 7:3 as determined by the amounts of end product isolated below.

One gram of this hydrogenation product containing 30,17a dihydroxyl6a-methyl-pregnane-l1,20-dione and 3a,17oc dihydroxy-l6fi-methyl-pregnane-11,20-dione, is chromatographed on 100 g. of activitated magnesium silicate. The 100% chloroform eluates give 3a,17adihydroxy-16rx-methyl-pregnane-11,20 dione, M.P. 188- 191 C. The methanol-chloroform eluates give 300, 17a dihydroxy l6,8-methyl-pregnane-11,20-dione, hexagonal plates from benzene-ethyl-acetate; M.P. 192- 197 C.

A solution of 3.50 g. (9.7 millimols) of 30,17oc-dihY- droxy-16,8-methyl-pregnane-11,20dione in 40ml. of chloroform is warmed to 40-45 C. A solution of 1.76 g. (11 millimols) of bromine in 25 ml. of chloroformis added dropwise to the stirred solution such that the color is not darker than pale yellow (ca. 2 drops/see, total.

time-1 hour). The nearly colorless solution is cooled to 20 C. and 200 m1. of ether is added. The mixture is extracted with excess cold 5% potassium bicarbonate solution, sodium bisulfite solution, and water, and dried over magnesium sulfate. The colorless residue after removal of solvent, 21 bromo 311,170: dihydroxy-16B- methyl-pregnane-l1,20-dione (about 4 grams) gives a positive tetrazolium test.

To 4.30 g. of 21-bromo-3a,17x-dihydroxy-16B-methylpregnane-11,20-dione in ml. of acetone and 0.01 ml. of acetic acid is added 4.83 g. of anhydrous potassium acetate and 3.85 g. of potassium iodide. The stirred mixture is refluxed for 18 hours and concentrated on the Water pump to a small volume. Water is added, the product extracted into ethyl acetate, and the organic extract dried over magnesium sulfate to give about 4 grams of a colorless foam that partly crystallizes from acetone-ether to give 3a,17oc,21 trihydroxy-l6 3-methyl-pregnane-11,20- dione 21-acetate.

To a solution of 3a,17a,2l-trihydroxy-l6fl-methyl-pregnane-11,20-dione 21-acetate (4.0 g.) in ml. t-butanol and 20 ml. of water cooled to 10-15 C., is added 3.5 g. N-bromo-succinimide. The suspension is stirred at 15C.

until all the N-bromosuccinimide has dissolved (90* min-' of acetic acid and 8 ml. of chloroform kept at 10 C.-

is added slowly 230 mg. of bromine in 6 ml. of chloroform. After addition is complete, 1.2 g. of sodium acetate in 7 ml. of cold water is added and the mixture is extracted with chloroform. The chloroform extract is washed with dilute potassium bicarbonate, water and dried over sodium sulfate. The residue is tritur-ated with ether to give 480 mg. of crystalline 4-bromo-17a,2l-dihydroxy-l6 3-methylpregnane-3,1'1,20-trione 21-acetate M.P. 170 C. dec.

To 583 mg. of 4-bromo-17a,21-dihydroxy-16,8-methylpregnane-3,11,20trione 21-acetate in 20 ml. of aceto nitrile under nitrogen is added a slurry of 600 mg. of semicarbazide hydrochloride and 410 mg. sodium bicarbonate in 4 ml. of Water. After 2 hours, the acetonitrile is removed in vacuo, water is added and about 540 mg. of cyrstalline 3-semicarbazone of 17a,2l-dihydroxy-16B- methyl 4 pregnene-3,11,20-trione 21-acetate filtered, washed with water and dried.

540 mg. of the 3-semicarbazone of 17a,21-dihydroxy- 16fi-methyl-4-pregnene-3,11,20-trione 21-acetate is dissolved in 20 ml. of acetic acid, 1.5 ml. of pyruvic acid and 5 ml. of water. After 18 hours at 25 0., Water is added and the mixture extracted with chloroform. The chloroform extract is washed with aqueous potassium bicarbonate, water and dried over sodium sulfate. Re moval of solvent gives crude 17u,21-dihydroxy-16/3-methyl-4-pregnene-3,11,20-trione 21-acetate which is purified by chromatography on neutral alumina and crystallization from acetone-ether (hexagonal plates). The pure material has M.P. 226232 C. 100 mg. of 17oc,21dihydroxy-l6B-methyl-4-pregnane-3,11,20-trione 21-acetate in 3 ml. of methanol is treated with 0.1 g. of potassium bicarbonate in 1 ml. of water, the methanol is evaporated in vacuo, and the residual material is extracted with ethyl acetate. Evaporation of the ethyl acetate solution gives crystalline 17a,21 dihydroxy 166- methyl-4-pregnene- 3 ,l1,20-trione.

To a stirred solution of 500 mg. of 17a,21-dihydroxy- 16fl-methyl-4-pregnene-3,11,20-trione 21-acetate in 12.5 ml. of methanol and 3 ml. of dimethylformamide kept under nitrogen is added a slurry of 680 mg. of semicarbazide hydrochloride and 370 mg. of sodium bicarbonate in 1 ml. of Water. The stirred mixture is refluxed 3 /2 hours and maintained at 45 C. for 17 hours. It is then 19 cooled to 20 C. and 50 ml. of 50% saturated aqueous sodium chloride is added. After 2 hours at C. the precipitate of 3,20-bis-semicarbazido 17a,21-dihydroxy- 16fl-methyl-4-pregnene 3,11,20-trione 21-acetate is filtered, washed with water until free of chloride ion and dried in air.

To a stirred solution of 600 mg. of 3,20-bis-semicarba- Zid017oc,2 l-dihydroxy-l 6fi-methyl-4-pregnene-3 ,11,20-trione 21-acetate in 30 ml. of tetrahydrofuran and 11 ml. of water under nitrogen is added 200 mg. powdered sodium borohydride. The stirred suspension is refluxed 45 minutes and then cooled to 15 C. Aqueous acetic acid ('3 ml. of 30%) is added cautiously and most of the tetrahydrofuran is removed in vacuum. Addition of ml. of methanol and 5 ml. of water induces the product to crystallize. Following addition of ml. of a saturated sodium chloride solution and aging at 0 C. the product 3, -bis-semicarbazido 11B,17ot,2l-trihydroxy- 16fl-methyl-4-pregnene-3,20-dione is filtered, washed with Water, and dried in air.

To a solution of 510 mg. of reduced 3,20-bis-semicar bazido 11fl,17ot,21-trihydroxy l6,8-methyl-4-pregnene- 3,20-dione in 5 ml. of acetic acid is added 1.20 ml. of water and 0.50 ml. of pyruvic acid. The solution is kept at C. for eighteen hours. Water (20 ml.) is added, and the mixture is extracted thoroughly with chloroform. The chloroform extract is dried over magnesium sulfate and taken to dryness. The residue is crystallized from acetone-ether to give pure 11fl,17a,21-trihydroxy-16fl-methyl-4-pregnene-3,20-dione. A solution of 100 mg. of 11B,17ot,2l-trihydroxy-16fi-methyl-4-pregnene- 3,20-dione in 1.0 ml. of pyridine and 0.5 ml. of acetic anhydride is prepared. After 18 hours at 25 C., the solution i taken to dryness in vacuo and the solid residue purified by crystallization from acetone-ether to give llfl,l7u,2l-trihydroxy 16B-methyl-4-pregnene-3,ZO-dione 21-acetate.

A solution of 400 mg. of 116,17a,2l-trihydroxy-l6 3- methyl-4-pregnene-3,20-dione 21-acetate in 2.0 ml. dimethyl formamide, 0.8 ml. of pyridine and 0.4 ml. of methanesulfonyl chloride is kept at 75 C. for one hour. The mixture is cooled, water added, and the precipitate filtered, washed with Water and dried in air. The desired 17u,21-dihydroxy-16,8-methy1-4-,9(11)-pregnadiene- 3,20-dione 21-acetate is purified by chromatography on alumina (20 g.) and elution of the column with benzene. Crystallization of material eluated by benzene gives pure 17u,21-dihydroxy-16fi-methyl 4,9(1 1)-pregnadiene3,20- dione 21-acetate.

To a mixture of 620 mg. of 17u,21-dihydroxy-16,L=I- methyl 4,'9(11)-pregnadiene 3,20-dione 21-acetate and 330 mg. of N-bromosuceinirnide in 10 ml. of dioxane and 3.2 ml. of water cooled to 10 C. is added 1.8 ml. of cold 1 M aqueous perchloric acid. The mixture is stirred at 15 C. for 3 hours. Excess N-bromosuccinimide is destroyed by addition of aqueous sodium thiosulfate and most of the dioxane is removed in vacuo. About ml. of water is added and crystalline bromohydrin, 9a-bromo- 1 1e, 17a,21-trihydroxy-16B-methyl-4-pregnene-3 ,20-dione 21-acetate, is filtered, washed with water, and dried in air.

To a stirred solution of 100 mg. of the 9a-bromo- 1 1/3,17a,21-trihydroxy-16,8methyl-4-pregnene-3 ,20-dione 21-acetate in 3 ml. of tetrahydrofuran and 1 ml. of methanol under nitrogen is added 1.02 ml. of 0.21.5 N methanolic sodium methoxide. After 10 minutes at 25 C., 0.2 ml. of-acetic acid is added and the methanol removed in vacuo. The residue is acetylated with 1.00 ml. of pyridine and 0.5 ml. of acetic anhydride at 60 C. for 70 minutes. The mixture is taken to dryness in vacuo, water added, and the product extracted into chloroform. The residue is crystallized from ether-acetone to give pure 95,1l e-epoxy-17u,21-dihydroxy-16B-methyl- 4-pregnene-3,20-dione 21-acetate.

To a. solution of 200 mg. of 913,11B-epoxy-17a,21-dihydroxy-16/3-methyl-4-pregnene-3,20-dione 21-acetate in 2 ml. of chloroform and 2 ml. of tetrahydrofuran in a polyethylene bottle at 60 C. is added 2 ml. of a 2:1 (by Weight) mixture of anhydrous hydrogen fluoride and tetrahydrofuran. After 4 hours at 10 C. the mixture is cooled to 60 C. and cautiously added to a stirred mixture of 30 ml. of 25% aqueous potassium carbonate and 25 ml. of chloroform kept at 5 C. The aqueous phase is further extracted with chloroform and the latter phase washed with water and dried over magnesium sulfate. The residue on crystallization from acetone-ether gives pure 9wflUOIO-l 15,17u,21-trihydroxy-16B- methyl-4-pregnene-3,20-dione 21-acetate.

To a stirred solution of 1.10 mg. of 9oz-fiu0r0-1 15,17a, 21-trihydroxy-16B-methyl-4-pre-gnene-3,20-dione 2'1-acetate in 5 ml. of methanol under nitrogen at 25 C. is added 1.00 ml. of 0.26 M methanolic sodium methoxide. After 15 minutes, 0.2 ml. of acetic acid in 1 ml. of water is added and the mixture concentrated nearly to dryness. The residue is taken up in ethyl acetate and the ethyl acetate solution is washed with Water, dried over magnesium sulfate, and concentrated to dryness. Crystallization of the residue from ethyl acetate gives pure 9a-fluoro-11fi, 1'7a,21-trihydroxy-16,8-methyl 4-pregnene-3,20-dione.

To a solution of mg. of 95,11fl-epoxy-17a,21-dihy droxy l6fi-methyl-4-pregnene-3,20-dione 21-acetate in 4 ml. of chlorofrom is added 5 ml. of concentrated hydrochloric acid. The two phase mixture is stirred at 25 C. for 1 hour. Addition of Water and chloroform extraction gives a crude crystalline product which is partly deacetylated. Treatment with 1 ml. of yridine and 0.5 ml. of acetic anhydride at 25 C. for 18 hours followed by concentration in vacuo and crystallization of the residue from acetone-ether affords pure 90c-ChlOIO-1-1fi,17ot, 21-trihydroxy 16,8 methyl-4-pregnene-3,20-dione 21-acetate. This compound is hydrolyzed by treatment with potassium bicarbonate in aqueous methanol to give 9u-chloro-11fi, =17 ,2 1 -trihydroxy-1 6(3-methyl-4-pregnene-3 ,20-dione.

To a stirred solution of 682 mg. of 17u,21-dihydroXy- 16fl-met-hyl-pregnane-3,11,20-trione 21-acetate in 20 ml. of chloroform and 2.25 ml. of acetic acid maintained at -20 C. is added dropwise one-half of a solution of 54 0 mg. of bromine in 2 ml. of chloroform and 3 ml. of acetic acid. -T he mixture'is warmed to 0 C. and the remainder of the bromine added. Sodium acetate (0.4 g.) in 2 ml. of water is added followed by 20 mg. of sodium sulfite. The mixture is concentrated in vacuo to remove the chloroform and 20 ml. of water is added. The white powdery precipitate of 2,4-dibromo-17u,21-dihydroxy-16fl-methylpregnane-3,1i1,20-trione 21-acetate is filtered, washed with water and dried in air. Yield: 920 mg. M.P. 122- C. dec.

To a solution under nitrogen of 900 mg. of the 2,'4-dibromo :,21 dihydroxy-l6fi-methylpregnane-3g11,20- trione 21-acetate in 5 ml. dimethyl formamide is added 200 mg. of sodium bromide. After 1 hour at 25 C., 1 ml. of dimethylaniline is added and the mixture maintained at 135 C. for 2 /2 hours. The mixture is cooled, added dropwise to dilute hydrochloric acid, and solid crude product filtered, washed with dilute hydrochloric acid, water and dried in air. Treatment with charcoal, followed by crystallization from acetone g-iv-es 1700,21-di-hY-dIOXY-16flmethyl 1,4-pregnadiene-3,11,20-trior1e ZI-a-cetate M.P. 230233 C.

1. 0 g. of 17a,21-dil1ydroxy-16,8-methyl-1, 4-pregnadiene- 3,11,20-tri one 2l-acetate in 30 ml. of methanol is treated With 1 g. of potassium bicarbonate in 10 ml. of water under nitrogen at reflux temperature for 7 minutes. The mixture is cooled, neutralized with 1 ml. of acetic acid in 10 ml. of water, the methanol removed in vacuo and the product extracted into ethyl acetate. Removal of the ethyl acetate gives crystals (about 0.9 g.) of the desired 17u,21-dihydroxy l6B-rnethyl-1,4-pregnadiene-3,11,20-trione; MJP. 200 C.

To 100 mg. of 11B,1704,21-trihydroxy-165-methyl-4- pregnene-3,20-dione 21-acetate in 5 ml. of acetic acid is added 50 mg. of selenium dioxide. The mixture is re fiuxed under nitrogen 18 hours, 50 mg. of selenium dioxide is added and the mixture refluxed an additional 24 hours. The mixture is filtered, and the filtrate taken to dryness. The residue is taken up in ethyl acetate and washed successively with aqueous sodium bicarbonate, ammonium sulfide, dilute ammonia water, water, dilute hydrochloric acid and water and dried over magnesium sulfate. It is then treated with activated charcoal and concentrated to dryness. Crystallization of the residue from acetoneether gives pure 1l5,17a,2.1-trihydroxy-loft-methyl-1,4- pregnadiene-3,20-dione 21-acetate. 100 mg. of 1l 3,17a, 211-trihydroxy-16B-methyl-1,4-pregnadiene 3,ZO-dione 21- acetate in 3 ml. of methanol is treated with 0.1 g. of potassium bicarbonate in 10 'ml. of water under nitrogen at reflux temperature for 7 minutes. The mixture is cooled, neutralized with 0.1 ml. of acetic acid in 1 ml. of water, the methanol is evaporated in vacuo and the residual material is extracted with ethyl acetate. Evaporation of the ethyl acetate gives crystalline 1lB,17oc-2 1-trihydroxy-16flmethyl-1,4 pregnadiene-3,20-dione.

In a similar manner, 100 mg. of 9a-fluorollfi,17u,21- trihydroxy-16B-methyl-4-pregnene-3,ZO-dione ill-acetate is treated with selenium dioxide to produce the corresponding 9u-fiuoro-ll l B,17u,2l-trihydroxy-l6,8-methyl-1,4-pregnadiene-3,20-dione 2 l-acetate. This compound is hydrolyzed with potassium bicarbonate in aqueous methanol in accordance with the procedure. described in the preceding paragraph to give 9a-fillO10-1 113,17a,21-trihydroxy-l6fimethyl-1,4-pregnadiene-3,ZO-dione. Similarly, 100 mg. of 90a chloro-1 l 3,17a,21-trihydroxy-16,8-methyl-4-pregnene- 3,2-dione 2lacetate is treated with selenium dioxide to produce 9oc-Cl1l0I'0-l 1 p), 17 a,21-trihydroxy- 16,B-methyl-1,4- pregnadiene-3,20-dione 2l-acetate, which is hydrolyzed by treatment with potassium bicarbonate in aqueous methanol to give 9a-chloro- 1'1/3,17a,2l-t1i=hydroxy-lop-methyl-1,4- pregnad-iene-3,20-dione.

A solution of 100 mg. of 9a-fiuoro-l1,8, 17a,2i1-trihydroxy-l6,8-methyl-1,4-pregnadiene3,20-dione 21-acetate in [1 ml. of pyridine is added to the complex formed by the addition of 100 mg. of chromium trioxide to 1 ml. of pyridine. The mixture is swirled until thoroughly mixed and then allowed to stand at room temperature overnight. The reaction mixture is poured into water, and the aqueous mixture is extracted with ether and then twice with ethyl acetate. The combined ether and ethyl acetate extracts are washed with dilute aqueous sulphuric acid at about 0 C., and then with water until neutral. The organic solvent layer is then dried, the solvents are evaporated therefrom in vacuo, and the residual crystalline material is purified by crystallization from ethyl acetate-ether to give 9a-fluoro-l7u,21-dihydroxy- 16,8-methyl-1,4-pregnadiene 3,1-1,20-trione 21-acetate. Ths compound is hydrolyzed by treatment with potassium bicarbonate in aqueous methanol to form 9a-fluoro17u,2l-dihydroxy-16fi-methy 1,4-pregnadiene-3,'l 1,20-trione.

In a similar manner, 9a-chloro-l1B,17u,21-trihydroxy- 1Gfl-methyl-1,4-pregnadiene-3,20-dione 21-acetate is reacted with chromium trioxide-pyridine complex to give 9oc-ChlO1'O-l7or,21 dihydroxy-l6/3-methyl-l,4-pregnadiene- 3,11,20-trione 21-acetate, which is hydrolyzed by treatment with potassium bicarbonate in aqueous methanol to give 9a-chloro-17a,2l-dihydroxy-16fi-methyl-L4-pregnadiene-3,1 1,20-trione.

Similarly, 9u-fluoro-l 1fi,l7a,21-trihydroxy-16fl methyl- 4-pregnene-3,20-dione 2l-acetate is reacted with chromium trioxide-pyridine complex to form 9oz-fl1lOlO-17a,21- dihydroxy l6fl-methyl-4-pregnene-3,11,20-trione 2l-acetate which is hydrolyzed by treatment with potassium bicarbonate in aqueous methanol to produce 9OL-flUOI'O- 17a,21-dihydroxy-16B-methyl-4-pregnene-3,1 1,20-trione.

Similarly, 9a-chloro-1 1B,17:,2l-trihydroxy-16B-methyl- 4-pregnene-3,20-dione 2l-acetate is reacted with chromium trioxide-pyridine complex to form 9a-chloro-17tx,2ldihydroxy 16p-methyl-4-pregnene-3J1,20-trione 21-ace- 22 tate which is hydrolyzed by treatment with potassium bicarbonate in aqueous methanol to produce 9a-chloro- 17a,21-dihydroxy-l6fi-methyl-4-pregnene-3,l1,20-trione.

10 grams of 17a,2l-dihydroxy-16a-methyl-4-pregnene 3,11,20-trione which can be prepared as described hereinabove, are dissolved in 400 cc. of chloroform. To this solution is added a mixture of cc. of concentrated aqueous hydrochloric acid and 100 cc. of 37% aqueous formaldehyde solution. The resulting mixture is stirred for a period of approximately 3 days at room temperature. The chloroform layer is separated, washed with sodium bicarbonate solution until neutral, then with water, dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo. The residual crude material is purified by crystallization from a mixture of methylene chloride and methanol to give 17ot,20,20,21-bismethylenedioxy-16oimethyl-4-pregnene-3,1 l-dione.

10 grams of 17u,20,20,21 bismethylenedioxy 16ozmethyl-4-pregnene-3,11-dione are dissolved in 500 cc. of benzene, to the solution is added 25 cc. ethylene glycol and 1 gram of p-toluenesulfonic acid, and the resulting mixture is heated under reflux for a period of approximately 15 hours. The reaction solution is cooled, washed with aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo. The residual crude material is absorbed from its solution in benzene on 250 g. of acid-washed alumina, and the resulting adsorbate is eluted utilizing mixtures of ether petroleum ether to give 3-ethylenedioxy-l7a- 20,20,2l-bismethylenedioxy 16wmethyl-5-pregnene-11- one.

A mixture 0f 10 grams of 3-ethylenedioxy-l7a,20,20,2lbismethylenedioxy-16a-methyl-5-pregnene-1l-one, 4.3 g. perbenzoic acid and 230 cc. benzene is allowed to stand at room temperature for a period of about 2 days. A portion of the epoxide product, which precipitates, is separated from the reaction solution by decantation, and the decanted solution is washed with saturated aqueous sodium bicarbonate solution and then dried over anhydrous sodium sulfate. The dried solution is then evaporated in vacuo, and the residual epoxide product is combined with the epoxide product originally separated from the reaction mixture.

The mixed epoxides are dissolved in 200 cc. of substantially anhydrous formic acid and the resulting solution is allowed to stand at room temperature for a period of about 2 /2 hours. The reaction solution is poured into water, and the aqueous mixture is extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and evaporated in vacuo to give a mixture of 17a,20,20,21-bismethylenedioxy-5-hydroxy- 16oz methyl-6-formyloxy pregnane 3,11-dione and 17a,20,20,21 bismethylenedioxy-6-hydroxy-16a-methyl-5- formyloXy-pregnane-3, 1 l-dione.

This mixture of 5-formyloxy and 6-formyloxy derivatives is dissolved in about 850 cc. of methanol, to this solution is added a solution containing about 17 grams of potassium hydroxide in 80 cc. of water, and the resulting mixture is heated under reflux in a nitrogen atmosphere for a period of approximately /2 hour. The reaction solution is cooled, neutralized with about 23 cc. of acetic acid and evaporated in vacuo to a small volume. The concentrated solution is poured into water and the aqueous mixture is extracted with chloroform. The chloroform extract is washed with aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo. The residual material is crystallized from methanol to give 17ot-20,20,21-bismethylenedioxy-16ot-methyl-allopregnane-El,6, 1 l-trione.

A solution containing about 5 grams of l7u,20,20,21- bismethylenedioxy 160a methyl allopregnene 3,6,11- trione and 0.1 g. of p-toluenesulfonic acid in cc. butanone dioxolane is heated under reflux for a period of about 10 minutes. The reaction solution is cooled to 4.3 about 5 C., diluted with chloroform, and the resulting solution is washed with aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The

resulting dried solution is evaporated to dryness in vacuo,

and the residual material is slurried with ether, recovered by filtration and then dried to give 3-ethylenedioxy- 17a,20,20,2l-bismethylenedioxy 16o: methyl-allopregnane-6,1l-dione.

A solution containing about grams of 3-ethylenedioxy-17a,20-20,2l-bismethylenedioxy 16ot-methyl-allopregnane-6,11-dione in 70 cc. of benzene is added, with stirring over a period of approximately minutes, to an ethereal solution containing the methyl magnesium iodide, prepared from 5 cc. of methyl iodide and 0.5 gram of magnesium turnings, dissolved in 50 cc. of ether. The reaction mixture is allowed to stir for an additional /2 hour period, and the resulting solution is decomposed with 70 cc. of water. About 170 cc. of benzene is added to the aqueous mixture and the layers are separated. The aqueous layer is extracted with two 100 cc.-portions of chloroform, and the organic layers are combined, dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo to give 3-ethylenedioxy-17a,20,20,2l-bismethylenedioxy-6fi-hydroxy-6a, 16a-dimethylallopregnane-1 l-one.

A solution containing 5.5 cc. of freshly distilled thionyl chloride in 26 cc. of cold anhydrous pyridine is added dropwise, with stirring, to a solution of 5.0 g. of 3-ethylenedioxy-17a,20,20,2l-bismethylenedioxy 6p hydroxy- 6a,16ot-dimethyl-allopregnene-1l-one in 32 cc. of anhydrous pyridine, while maintaining the temperature of the reaction mixture at approximately 40 C. The reaction solution is stirred for an additional 30 minute period following the addition of the thionyl chloride reagent, and the reaction mixture is then cooled to about 05 C. and poured into 180 cc. ice water. The aqueous mixture is extracted with chloroform, and the chloroform extract is neutralized, dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo. The residual material, dissolved in benzene, is chromatographed on 150 grams of acid-washed alumina; elution of the resulting adsorbate with mixtures of petroleum ether and ether gives 3-ethylenedioxy-17a,20,20,21 bismethylenedioxy-6,16- dimethyl-S -pregnene-1 l-one.

A solution containing about 5 grams of 3-ethylenedioxy-17u,20,20,2l-bismethylenedioxy 6,16a-dimethyl-5- pregnene-ll-one, 500 cc. of anhydrous acetone and about 0.5 g. of p-toluenesulfonic acid monohydrate is allowed to stand for a period of about hours. The reaction solution is poured into water, and the aqueous mixture is extracted with chloroform. The chloroform solution is washed with aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the chloroform solution is evaporated to dryness in vacuo. The residual material is crystallized from benzene to give 17u,20,20,21- bismethylenedioxy 606,1606 dimethyl 4-pregnene-3,11- dione.

About 0.1 gram of 17a,20,20,2l-bismethylenedioxy- 6a,16a-dimethyl-4-pregnene-3,1l-dione is suspended in 18 cc. of 50% aqueous acetic acid, and the suspension is carefully purged with nitrogen, following which the suspension is heated on a steam bath under nitrogen for a period of about 8 hours and then allowed to stand at room temperature for an additional period of 15 hours. The reaction solution is evaporated to dryness in vacuo to give 17a,21-dihydroxy-6a,16a-dimethyl 4 pregnene- 3,11,20-trione. The material is dissolved in 20 cc. of chloroform, and the chloroform solution evaporated to dryness in vacuo. To the residual dry material is added 1 cc. of pyridine and 1 cc. of acetic anhydride, and the resulting mixture is heated on a steam bath for a period of about 15 minutes. The reaction solution is cooled to about 05 C. and poured into ice water. The aqueous suspension is extracted with chloroform, and the chloroform extract is washed with aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo. The residual material, dissolved in 30 cc. benzene, is adsorbed on 5 grams of acidwashed alumina; the adsorbate is washed with cc. ether. The adsorbate is then eluted with 250 cc. of a 5:5 mixture of ether-chloroform, and then with 50 cc. of a 3:7 mixture of ether-chloroform. The eluates are evaporated in vacuo, and the residual material is crystallized from methanol to give 17a,21-dihydroxy-6a,16u-dimethyl- 4-pregnene-3,1 1,20-trione 21-acetate.

In accordance with the foregoing procedures, but starting with 17a,21 dihydroxy 16fl methyl 4 pregnene- 3,11,20-trione, there are obtained the corresponding 1704-21-dihydroxy-6u,16B-dimethyl 4 pregnene-3,1l,20- trione and its 21-acetate.

To a solution of 100 mg. of 17u,2l-dihydIOXy-6u,16ocdirnethyl-4-pregnene-3,11,20-trione ZI-acetate, in 6 ml. tbutanol, and 0.01 ml. of glacial acetic acid is added mg. of selenium dioxide. The mixture is heated under reflux in a nitrogen atmosphere for a period of about 6 hours. The reaction solution is filtered and evaporated in vacuo. The residual material is dissolved in benzene, and the benzene solution is washed with an aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The benzene solution is stirred with mercury overnight, then centrifuged, and the clear benzene solution is evaporated in vacuo. The residual material thus obtained is separated using partition chromatography on diatomaceous silica (Super-Cel) to give 17a,21-dihydroxy-6a,16a-dimethyl-1,4-pregnadiene-3,11,20-trione 21- acetate. 40 mg. of 17u,21-dihydroxy-6a,16a-dimethyl- 1,4-pregnadiene-3,11,20-trione 21-acetate is dissolved in a mixture of 1.0 cc. of benzene and 1.0 cc. of 1 N methanolic potassium hydroxide, and the solution is allowed to stand at room temperature for a period of about 10 minutes. The solution is then acidified with acetic acid, then benzene is evaporated in vacuo, and the residual material is purified-by crystallization to give 17u,21-dihydroxy-6oz,16a-dimethyl-1,4-pregnadiene-3,1 1,20-trione.

Similarly, in accordance with the foregoing procedure, but starting with 17a,21-dihydroxy-6or,16fi-dimethyl-4- pregnene-3,11,20-trione 21-acetate, there are obtained the corresponding 17a,21dihydroxy 60:,16fl dimethyl-1,4- pregnadiene-3,11,20-trione, and its 21-acetate.

About 5 grams of 3-ethylenedioxy-17a,20-20,21-bismethylenedioXy-6,16a-dimethyl-5-pregnene-1 l-one, which can be prepared as described hereinabove, is dissolved in about cc. of benzene. This solution is added to a stirred suspension containing 5 grams of lithium aluminum hydride in one liter of anhydrous ether, and the resulting suspension is heated under reflux for a period of about 4 hours. The reaction mixture is allowed to cool to about room temperature, and approximately 33 cc. of ethyl acetate is added to destroy excess lithium aluminum hydride. The resulting mixture is admixed with about cc. of water, the ethereal layer is decanted, and the aqueous layer, diluted with an additional 200 cc. of Water, is extracted with chloroform. The ether and chloroform layers are combined, and the combined organic layers are dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residual material, dissolved in about 250 cc. of benzene, is adsorbed on about grams of acid-washed alumina, and the resulting adsorbate is eluted utilizing mixtures of petroleum ether-ether. This eluate is evaporated in vacuo, and the residual material is purified by crystallization from. ether to give 3-ethyl enediOXY-17oc,20,20,21 bismethylenedioxy 11/3-hydroxy- 6,16ct-dimethyl-5-pregnene.

A solution containing about 5 grams of 3-ethylenedioxy 17a,20,20,21 bismethylenedioxy-1113 hydroxy-6, l6a-dimethyl-5-pregnene, 500 cc. of anhydrous acetone and about 0.5 g. of p-toluenesulfonic acid monohydrate is allowed to stand for a period of about 15 hours. The reaction solution is poured into Water, and the aqueous mixture is extracted with chloroform. The chloroform solution is washed with aqueous sodium bicarbonate solution,

25 dried over anhydrous sodium sulfate, and the chloroform solution is evaporated to dryness in vacuo. The residual material is crystallized from benzene to give 17a,20,20,21- bismethylenedioxy-llfi-hydroxy 6a,16a-dimethy1-4-pregnene-3-one.

About 0.1 gram of 17a,20,20,21-bismethylenedioxyllfi-hydroxy 60:,l6oc-dll'fi6tl'lYl-4 pregnene-3-one is suspended in 18 cc. of 50% aqueous acetic acid, and the suspension is carefully purged with nitrogen, following which the suspension is heated on a steam bath under nitrogen for a period of about 8 hours and then allowed to stand at room temperature for an additional period of 15 hours. The reaction solution is evaporated to dryness in vacuo to give 11/3,17a,21-trihydroxy-6a,16a-dimethyl- 4-pregnene-3,20-dione. This material is dissolved in 20 cc. of chloroform, and the chloroform solution evaporated to dryness in vacuo. To the residual dry material is added 1 cc. of pyridine and 1 cc. of acetic anhydride, and the resulting mixture is heated on a steam bath for a period of about 15 minutes. The reaction solution is cooled to about -5 C. and poured into ice water. The aqueous suspension is extracted with chloroform, and the chloroform extract is washed with aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residual material, dissolved in 30 cc. benzene, is adsorbed on 5 grams of acid-washed alumina; the adsorbate is washed with 50 cc. ether. The adsorbate is then eluted with 250 cc. of a 5:5 mixture of ether-chloroform, and then with 50 cc. of a 3:7 mixture of ether-chloroform. The eluates are evaporated in vacuo, and the residual material is crystallized from methanol to give 11B,l7a,2l-trihydroxy-6a,16a dimethyl-4-pregnene- 3,20-dione 21-acetate.

In accordance with the foregoing procedure, but starting with 3-ethylenedioxy-l7a,20,20,2 l-bismethylenedioxy- 6,16/3-dimethyl-5-pregnene-1l-one (which is obtained as an intermediate in the preparation of 17a,21-dihydroxy- 6a,16fi dimethyl-4-pregnene 3,11,20-trione 2l-acetate herein described above), there are obtained the corresponding 11,8,l7a,2l-trihydroxy-6a,l6p dimethyl-4-pregnene-3,20-dione and its 2l-acetate.

To a solution of 100 mg. of 11fl,17a,21-trihydroxy- 6a,l6a-dimethyl-4-p1'egnene-3,20-dione 21-acetate in 6 ml. t-butanol, and 0.01 ml. of glacial acetic acid, is added 70 mg. of selenium dioxide. The mixture is heated under reflux in a nitrogen atmosphere for a period of about 6 hours. The reaction solution is filtered and evaporated in vacuo. The residual material is dissolved in benzene, and the benzene solution is washed with an aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The benzene solution is stirred with mercury overnight, then centrifuged and the clear benzene solution is evaporated in vacuo. The residual material thus obtained is separated using partition chromatography on diatomaceous silica (Super-Cel) to give 11,8,l7oc,2l trihydroxy-6u,16u dimethyl-l,4-pregnadiene 3,20-dione 2l-acetate. 45 mg. of 1l/3,l7u,21-trihydroxy-6a,16a dimethyl-1,4 pregnadiene 3,20-dione 21-acetate is dissolved in a mixture of 1.0 cc. of benzene and 1.0 cc. of 1 N methanolic potassium hydroxide, and the solution is allowed to stand at room temperature for a period of about minutes. The solution is then acidified with acetic acid, then benzene is evaporated in vacuo and the residual material is purified by crystallization to give l1fl,17a,2l.- trihydroxy-6a,l6a-dimethyl1,4-pregnadiene-3,20-dione.

Similarly, in accordance with the foregoing procedures but starting With l1fi,17a,21-trihydroxy-6a,16,8-dimethyl- 4-pregnene-3,20-dione 21-acetate, there are obtained the corresponding 1 1 5, 17 2 1-trihydroxy-6oc, l6fi-dimethyl- 1,4- pregnadiene-3,20-dione, and its 21-acetate.

To a cooled solution of 436 mg. of 11,8,l7a,21-trihydroxy-6a,16a-dimethyl-4-pregnene-3 ,ZO-dione 2 l -acetate (which can be prepared as described hereinabove) in 2.5 cc. dimethyl formamide and 2.0 ml. of dry pyridine is added 1.0 ml. of methane sulfonyl chloride, While maintaining the temperature below 0 C. The resulting mixture is allowed to warm to room temperature, at which point a precipitate appears; the resulting mixture is then heated to a temperature of about 100 C. for a period of about 10 minutes. About 15 ml. of water is added slowly to the reaction mixture, with stirring, and the aqueous mixture is extracted with eythl acetate. The com bined ethyl acetate extracts are washed with water, then with dilute aqueous hydrochloric acid solution, again with water, and then with a dilute aqueous sodium bicarbonate solution. The washed ethyl acetate solution is dried, and the solvent is evaporated in vacuo; the residual material is triturated with ether, and the crystalline material is recrystallized to give 17a,21-dihydroxy-6a,16a-dimethyl 4,9(1l)-pregnadiene-3,20-dione ZI-acetate. A suspension of 330 mg. of 17a,21-dihydroxy-6u,l6a-dimethyl-4,9(11)- pregnadiene-3,20-dione 2l-acetate and 1.8 g. of N-bromosuccinirnide in a mixture of 50 ml. of dioxane and 10 ml. of water is cooled to 10 C. Then with stirring, 10 ml. of cold 1.0 N aqueous perchloric acid is added. The temperature of the reaction mixture is allowed to rise to 15 C. and is maintained at this point for about two and one-half hours during which time the solid material slowly dissolves. The resulting yellow solution is treated with 1.0 ml. of allyl alcohol to discharge the color and the remaining N-bromo-succinimide, and the resulting solution is evaporated to a small volume in vacuo. The concentrated solution is diluted with water, and the aqueous mixture is extracted with ethyl acetate. The ethyl acetate extracts are washed, dried and evaporated to dryness, and the residual material is crystallized from ethyl acetate-ether to give 9a-bromo-11 8,17a,21-trihydroxy-6a,16oc-dirnethyl-4-pregnene-3,ZO-dione 21-acetate.

A soultion of 210 mg. of 9oc-bIO'II10-1l/3,17oc,21-1Iil1y droxy-6a,'l6a-dimethyl-4-pregnene-3,ZO-dione 2l-acetate and 240 mg. of potassium acetate in 10 ml. of absolute ethanol is heated under reflux for two hours. The reaction mixture is cooled to room temperature, evaporated in vacuo to a small volume, and diluted with water. The concentrated aqueous mixture is extracted with three portions of ethyl acetate, and the combined ethyl acetate extracts are washed with water, dried, and evaporated to dryness in vacuo. The residual material is crystallized from ethyl acetate-ether to give 9B,11fl-epoxy-17a,21-dihydroxy 6a,16oc-dimethyl-4-pregnene-3,ZO-dione 2l-acetate.

To a solution of 83 mg. of anhydrous hydrogen fluoride in 4.7 ml. of ice-cold alcohol-free chloroform is added an ice-cold solution of 416 mg. of 9fl,11,8-epoxy-17a,21- dihydroxy-6u,16a-dimethyl-4-pregnene-3 ,20-dione 2 l-acetate. The solution is mixed thoroughly and maintained at 0 C. for two hours, at the end of which time 13.0 ml. of ice-cold 20% aqueous sodium acetate is added, and the resulting mixture agitated vigorously. The layers are separated, and the chloroform layer is washed with water until free of acid, dried, and the chloroform evaporated in vacuo. The residual material is crystallized from acetone-petroleum ether to give 9a-fluoro-11B, 17a,21-trihydroxy-6a,16a-dimethyl-4-pregnene-3,ZO-dione ZI-acetate. Fifty milligrams of 9oc-filIOIO-l1fl,17oc,21trihydroxy 6a,l6a-dimethyl-4-pregnene-3,ZO-dione 21-acetate is dissolved in a mixture of 1.0 cc. of benzene and 1.0 cc. of 1 N methanolic potassium hydroxide, and the solution is allowed to stand at room temperature for a period of about 10 minutes. The solution is then acidi tied with acetic acid, the benzene is evaporated in vacuo, and the residual material is purified by crystallization to give 9a fiuoro-llB,17a,21-trihydroxy-6a,16a-dimethyl- 3,20-dione.

Similarly, when hydrogen chloride is substituted for" hydrogen fluoride in the reaction with 95,11,8-epoxy-l7a, 21 dihydroxy-6a,16a-dimethyl-4-pregnene-3,ZO-dione 21- acetate there is obtained the corresponding 9a-chloro-llfi, 1704-21 trihydroxy 6a,16ot-dimethyl-4-pregnene-3,20- dione.

In accordance with the foregoing procedures when 115, 17a,2l trihydroxy 6a,16fi-dimethyl-4-pregnene-3,20- dione 21-acetate is employed as the starting material, there is Obtained the corresponding 9OC-fiuOI'O-1 1B,l7ot,21-trihydroxy 60,16fi dim'ethyl-4-pregnene-3,20-dione or 90:- chloro 11,8,l7oc,2l trihydroxy-6nt,16p-dimethyl-4-pregnene-3,20-dione.

o a solution of 100 mg. of 9a-fiuoro-11,8,17oc,21-trihydroxy-6a,16a-dirnethyl-4pregnene-3 ,20-dione 21-acetate, in 6 ml. t-butanol, and 0.01 ml. of glacial acetic acid is added 70 mg. of selenium dioxide. The mixture is he'ated under reflux in a nitrogen atmosphere for a period of about 60 hours. The reacttion solution is filtered and evaporated in vacuo. The residual material is dissolved in benzene, and the benzene solution is washed with an aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The benzene solution is stirred with mercury overnight, then centrifuged, and the clear benzene solution is evaporated in vacuo. The residual material thus obtained is separated, using partition chromatography on diatomaceous silica (Super-cel), to give 9oz-flllOIO-llfl, 17oc,21 trihydroxy-6u-16u-dimethyld,4-pregnadiene-3,20- dione 21-acetate. I

This material is hydrolyzed using 1 N methanolic potassium hydroxide in benzene as described above for the hydrolysis of 9owfluoro-l1,8,17a,21-trihydroxy-6m,16a-dimethyl-4-pregnene-3,20-dione 2l-acetate to give 9 x-fluorol1}3,17oz,21 trihydroxy 6a,16a dimethyl-1,4-pregnadiene-3,20-dione.

Starting with 9oc-Chl0IO-1lfl,l7oz,21-l;IihydrOXy-6oc,16adimethyl-4-pregnene-3,20-dione 21-acetate, there are obtained in accordance with the foregoing procedures the corresponding 9oc-ChlOIO-l1B17u,2'1-lrihyd-1OXy-6a,160L-dlmethyl-1,4-pregnadiene-3,20-dione, and its 21-acetate.

Similarly, starting with 9oz bromo-l1B,17a,2l-trihydroxy 6a,l6a-dimethyl-4-pregnene-3,ZO-dione 21-acetate obtained as an intermediate in the preparation of 904- iluoro llfl,l7cc,2l trihydroxy-6a,l6a-dimethyl-4-pregnene-3,20-dione herein described above, there are obtained the corresponding 9a-bromo l1[3,l7oc,21 trihydroxy-6u, 16u-dimethyl 1,4 pregnadiene 3,20 dione, and its 21- acetate.

ln accordance with the foregoing procedures, but starting with 9a-halo-11B,17u,21-trihydroxy-6a,16fl-dimethyl 4-pregnene-3,20-dione 21-acetate there are obtained the corresponding 90c halo-11,8,17a,21-trihydroxy-6u,16fi-dimethyl-1,4-pregnadiene-3,20-diones such as for example 90c fluoro l1B,l7a,2l-trihydroxy-6u,16,8-dimethyl-L4- pregnadiene-3,20-dione, 9a-chloro-11fi,l7a-trihydroxy-6a,

16/i-dimethyl-1,4-pregn-adiene-3,20-dione and 9a-bromo- 11B,17a,21 trihydroxy-Ga,16f3-dimethyl-1,4-pregnadiene- 3,20-dione, and their 2l-acetates.

A solution of 400 mg. of 9a-fiuoro-11fi,17a,21-trihydoxy-6u,l6a-dimethyl-4-pregnene-3,20-dione 2l-acetate in 4 ml. of pyridine is added to the complex formed by the addition of 400 mg. of chromium trioxide to a. 4 ml. of p-yridine. The mixture is swirled until thoroughly mixed and then. allowed to stand at room temperature overnight. The reaction mixture is poured into water, and the aqueous mixture is extracted with ether and then twice with ethyl acetate. The combined ether and ethyl acetate extracts are washed with dilute aqueous sulfuric acid at about C., and then with water until neutral. The organic solvent layer is then dried, the solvents are evarporated therefrom in va-cuo, and the residual crystalline material is purified by crystallization to give 90L-fl11OIO-17oc, 21 dihydroxy-a,16ot-dimethyl-4-pregnene-3,11,20-trione 21-acetate. Fifty milligrams of 9a-fluoro-17u,21-dihydroxy 6a,16ozdimethyl-4-pregnene-3,11,20-tione 21-acetate is dissolved in a mixture of 1.0 cc. of benzene and 1.0 cc. of 1 N methanolic potassium hydroxide and the solution is allowed to stand at room temperature for a period of about minutes. The solution is then acidified with acetic acid, the benzene is evaporated. in vacuo, and the residual material is purified by crystallization to give 28 9a fluoro-17oc,2l-dihydroxy-6u,16a-dimethyl-4-pregnene- 3 ,1 1,20-trione.

Similarly, starting with 9a-chloro-11,8,17a,21-trihydroxy-6a,16a-dimethyl-4-pregnene-3 ,20-dione 21-acetate, there are obtained in accordance with the foregoing procedures the corresponding 9a-chlo'ro-l7a,2l-dihydroxy-6u, '16a-dimethyl-4-pregnene-3,l1,20-trione, and its 21-acetate.

Similarly, but starting with 9a-bromo-11B,17u,21-trihydroxy-6oc,16u-dimethyl-4-pregnene-3,20-dione 21-acetate obtained as an intermediate in the preparation of 9oc-flu0- ro 11,3,17oc,2l trihydroxy-6a,16a-dimethyl-4-pregnene- 3,20-dione herein described above, there are obtained the corresponding c bromo 17ot,21-dihydroxy-6a,16ot-dimethyl-4-pregnene-3,11,20-trione, and its 21-acetate.

In accordance with the foregoing procedures, but starting with 9a-halo-115,17a,21-trihydroxy-6a,16fi-dimethyl- 4-pregnene-3,20-dione 21-acetate, there are obtained the corresponding 9a-halo-17u,2l-dihydroxy-6a,16fi-dimethyl- 4-pregnene-3,11,20-triones, such as for example, 9a-fl1l0- r-o 17oc,2l dihydroxy-6oz,16,8-dimethyl-4-pregnene-3,11, 20-trione, 9a-chloro-17a,21-dihydroxy-6a,16B-dimethyl-4- pregnene-3,11,20-trione, and 9ot-bromo-17a,21-dihydroxy- 6a,].65-dimethyl-4-pregnene-3,11,20-trione and their 21- acetates.

To a solution of mg. of 9a-fluoro-l7a,2l-dihydroxy- 60c,16a-dimethyl-4-pregnene-3,11,20-trione ZI-acetate, in 6 ml. t-butanol, and 0.01 ml. of glacial [acetic acid is added 70 mg. of selenium dioxide. The mixture is heated under reflux in a nitrogen atmosphere for a period of about 60 hours. The reaction solution is filtered and evaporated in vacuo. The residual material is dissolved in benzene, and the benzene solution is washed with an aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The benzene solution is stirred with mercury overnight, then centrifuged, and the clear benzene solution is evaporated in vacuo. The residual material thus obtained is separated using partition chromatography on diatomaceous silica (Super-Gel) to give 9a-fluoro-17a, 21 :dihydroxy-6m,16a-dimethyl-1,4-pregnadiene-3,11,20- trione 21-acetate. This material is hydrolyzed using 1 N methanolic potassium hydroxide in benzene as described hereinabove for the hydrolysis of 9a-fiuoro-17a,21dihydroxy-6a,16ot-dime-thyl-4apregnene-3,11,20-trione 21 acetate to give 9a-fluoro-17a,21-dihyclroxy-6a,16a-dimethyll,4-pregnadiene-3 ,11,20-trione.

Similarly, starting with 9a-chloro-17a,2l-dihydroxy-6a, 16ot-dimethyl-4-pregne-ne-3,11,20-trione 21-acet-ate there are obtained in accordance with the foregoing procedures the corresponding 9tx-chloro-17a,21-dihydroxy-6u,l6a-dimethyl-1,4-pregnadiene-3,11,20-trione, and its Zl-acetate.

Similarly, but starting with 9a-bromo-17u,21-dihydroxy- 604,160 dirnethyl 4 pregame-3,1 1,20-trione 21-acetate there are obtained the corresponding 9a-bIOmO-l7a,21- dihydroxy 60:,160: dimethyl-1,4-pregnadiene-3,l1,20-trione, "and its 21-acetate.

In accordance with the foregoing procedures but starting with 911 halo-17u,21-dihydroxy-6a,16fl dimethyl-4-pregnone-3,11,20-trione 21-acetate there are obtained the corresponding 9a-halo-l7a,21-dihydroxy-6 x,16fi-di-methyl-L4- pregnadienes-3,l1,20-triones, such as for example, 9a-fluoro 17a,21-dihydroxy-6a,16B-dirnethyl-1,4-prgnadiene-3, 11,20-trione, 90L-Ch10lO-170t,21-d'lhydIOXy-60t,16fidlIl'lCllhyl-1,4-pregnadiene-3,11,20-trione and 9abI'0mO-17oz,21-dlhydroxy 6oz,16B-dimethyl-1,4-pregnadiene-3,l1,20-trione, and their 21-acetates.

A suspension containing 300 mg. of 17a,2l-dihydroxy- 6a,16a-dimethyl-4-pregnene 3,11,20 trione 2l-acetate, 700 mg. of chloranil, 8.3 ml. of ethyl acetate and 1.7 ml. of acetic acid is refluxed for 17 hours under nitrogen. The reaction mixture is diluted with 40 ml. of ethyl acetate and filtered. The filtrate is washed sequentially with two 20 ml. portions of ice cold 10% aqueous sodium bisulfite solution, three 20 ml. portions of ice cold 5% aqueous potassium hydroxide solution and finally washed to neutrality with several 20 ml. portions of ice water. The aqueous washes are re-extracted with 50 ml. of ethyl acetate and treated as above. The combined organic phase is dried over sodium sulfate and concentrated in vacuo. The crude material dissolved in benzene is chromatographed on 15 g. of acid-washed alumina. Elution with chloroformzether 2:8 affords 17a,2l-dihydroxy 6,160: dimethyl 4,6 pregnadiene- 3,11,20-trione 2l-acetate. This product is then hydrolyzed by treatment with a solution of potassium bicarbonate in aqueous methanol to form 170,21-dihydroxy- 6,160t-dimethyl-4,6-pregnadiene-3 ,1 1,20-trione.

In accordance with the above procedure but starting with 17a.,21-dihydroxy-60t,165 dimethyl 4-pregnene- 3,11,20-trione 21-acetate there are obtained 1706,21-dlhY- droxy-6,165-dimethyl-4,6-pregnadiene-3, 1 1,20-trione and its 21-acetate.

In accordance with the above procedure but starting with 1 15, l70z,21-trihydroxy-60t,160-dimethyl-4-pregnene 3,20-dione ZI-acetate there is obtained 115,170t,21-trihydroxy-6,16a-dimethyl-4,6-pregnadiene-3,20-dione and its 21-acetate. In accordance with the above procedure but starting with 1 15,170c,21-trihydroxy-60t,165-dimethyl-4-pregnene- 3,20-dione 21-acetate there is obtained 115,170t,21-trihydroxy-6,165-dimethyl-4,6-pregnadiene-3,20-dione and its 21-acetate.

'A suspension containing 300 mg. of 90t-fluoro-115,- 17a,21-trihydroxy-60t,160 dimethyl 4 pregnene-3,20- dione 2l-acetate, 700 mg. of chloranil, 8.3 ml. of ethyl acetate and 1.7 ml. of acetic acid is refluxed for 17 hours under nitrogen. The reaction mixture is diluted with 40 ml. of ethyl acetate and filtered. The filtrate is washed sequentially with two 20 ml. portions of ice cold 10% aqueous sodium bisulfite solution, three 20 ml. portions of ice cold 5% aqueous potassium hydroxide solution and finally washed to neutrality with several 20 ml. portions of ice water. The aqueous washes are re-extracted with 50 ml. of ethyl acetate and treated as above. The combined organic phase is dried over sodium sulfate and concentrated in vacuo. The crude material dissolved in benzene is chromatographed on 15 g.-of'acid-Washed alumina. Elution with chloroform: ether 2:8 affords 9a-fluoro-l15,170,21-trihydroxy-6,160cdimethyl-4,6-pregnadiene-3,20 dione 21-acetate. This product is then hydroylzed by treatment with a solution of potassium bicarbonate in aqueous methanol to form 90-fluoro-1l5,170t,21 trihydroxy 6,160 dimethyl-4,6- pregnadiene-3,20-dione.

In accordance with the above procedure but starting with 90t-chloro-115,17a,21-trihydroxy 6a,1600-dimethyl 4-pregnene-3,20-dione 21-acetate, there are obtained the corresponding 90t-chloro-l15,170 ,21-trihydroxy-6,160t-dimethyl-4,6-pregnadiene-3,20-dione and its 21-acetate.

In accordance with the above procedure but starting with 90t-bromo-l15,17u.,21-trihydroxy 6,1600 dimethyl-4- pregnene-3,20-dione 21-acetate, there are obtained the corresponding 90t-bromo-1 15,170;,21-trihydroxy-6,160t-dimethyl-4,6-pregnadiene-3,20-dione and its 21-acetate.

Similarly, in accordance with the above procedure but starting with 90t-fluoro-115,1700,21-trihydroxy 60:,165-dimethyl-4-pregnene-3,ZO-dione 2l-acetate, there is obtained the corresponding 90t-fluoro 115,170t,2l-trihydroxy-6,l65-dimethyl-4,6-pregnadiene-3,20-dione and its 21-acetate.

Similarly, in accordance with the above procedure but starting with 9a-chloro-115,17a,21-trihydroxy-60t,165- dimethyl-4-pregnene-3,20-dione 21-acetate, there is obtained the corresponding 9OL-Ch1OI'O 115,170t,21-trihydroxy-6,165-dimethyl-4,6-pregnadiene-3,20-dione and its 21-acetate.

Similarly, in accordance with the above procedure but starting with 90t-bromo-l15,170:,21-trihydroxy-60:,165-dimethyl-4-pregnene-3,20-dione 21-acetate, there is obtained the corresponding 9a bromo-115,170,21-trihy- 30 droxy-6,165-dimethyl-4,6-pregnadiene-3,20-dione and its 21-acetate.

A suspension containing 300 mg. of t-fluoro-1700,'21- dihydroxy-600, t-dimethyl-4-pregnene-3, 1 1, ZO-trione 21-acetate, 700 mg. of chloranil, 8.3 ml. of ethyl acetate and 1.7 ml. of acetic acid is refluxed for 17 hours under nitrogen. The reaction mixture is diluted with 40 ml. of ethyl acetate and filtered. The filtrate is washed sequentially with two 20 ml. portions of ice cold 10% aqueous sodium bisulfite solution, three 20 ml. portions of ice cold 5% aqueous potassium hydroxide solution and finally washed to neutrality with several 20 ml. portions of ice water. The aqueous washes are reextracted with 50 ml. of ethyl acetate and treated as above. The combined organic phase is dried over sodium sulfate and concentrated in vacuo. The crude material dissolved in benzene is chromatographed in 15 g. of acid-washed alumina. Elution with chloroform:ether 2:8 affords 90 fluoro ,2'1 dihydroxy 6,160; dimethyl 4, 6- pregnadiene-3,11,20-trione 21-acetate. This product is then hydrolyzed by treatment with a solution of potassium bicarbonate in aqueous methanol to form 90t-fluoro- 170:,21 dihydroxy 6,160z-dimethyl 4, 6 pregnadiene- 3,11,20-trione.

In accordance with the above procedure but starting with 90 chloro-17a,21-dihydroxy 60 160: dimethyl 4- pregnene-3,11,20-trione 21-acetate there is obtained the corresponding 9OL-ChlO1O 1706,21 dihydroxy 6,160 dimethyl 4,6 pregnadiene 3,11,20 trione and its 21- acetate.

In accordance with the above procedure but starting wih 9a-bromo 170:,21 dihydroxy 604,160 dimethyl 4 pregnene 3,11,20 trione 21 acetate there is obtained the corresponding 900 bromo 1704,21 dihydroxy- 6,1606 dimethyl 4,6-pregnadiene 3,11,20 trione and its ZI-acetate.

Similarly, in accordance with the above procedure but starting with 90 fluoro 170:,21 dihydroxy 60;,165- dimethyl 4 pregnene 3,11,20-trione 21 acetate, there are obtained the corresponding 90c fluoro 1706,21 dihydroxy 6,165 dimethyl 4,6 pregnadiene 3,11,20- trione and its 21-acet-ate.

Similarly, in accordance with the above procedure but starting with 90: chloro 1761,21 dihydroxy 60:,165

dimethyl 4 pregnene 3,11,20 trione 21 acetate, there are obtained the corresponding 90 chloro 1706, 21 dihydroxy 6,165 dimethyl 4,6 pregnadiene-3, 11,20-trione and its 21-acetate.

Similarly, in accordance with the above procedure but starting with 90 bromo 1706,21 dihydroxy 60:,165 dimethyl 4-pregnene 3,11,20 trione 21 acetate, there are obtained the corresponding 90 'bromo 1706,21- dihydroxy 6,165 dimethyl 4,6 pregnadiene 3,11,

20-trione and its 21 acetate.

To a solution of 200 mg. of 17a,21-dihydroxy-6,160cdimethyl 4,6 pregnadiene 3,11,-20-trione 21 acetate in 0.16 ml. of acetic acid and 12 ml. of t-amyl alcohol is added 120 mg. of selenium dioxide and 2 drops of mercury. The mixture is refluxed under nitrogen overnight. The solution is filtered, washed with sodium bicarbonate, dried, and concentrated. This product is chromatographed on acid-washed alumina. The absorbate is eluted with mixtures of chloroform and ether, increasingly rich in chloroform. The elu-ates are combined, evaporated to dryness and the residual material recrystallized from ethyl acetate to give 1701,21 dihydroxy 6, 16a dimethyl 1,4,6 pregnatriene 3,11,20 trione 21- acetate. This product is then hydrolyzed by treatment with a solution of potassium bicarbonate in aqueous methanol to form 17a,21-dihydroxy 6,1606 dimethyl 1,4,6-

pregnatriene 3,11,20 trione.

In accordance with the above procedure but starting with 170t,21 dihydroxy 6,165 dimethyl 4,6-pregnadiene 3,11,20 trione 21 acetate there are obtained 31 17a,21 dihydroxy 6,16f3 dimethyl 1,4,6 pregnatriene-3,11,20-trione and its 21-acetate.

Similarly, when 11/3,l7u,21 trihydroxy 6,16a dimethyl 4,6 pregnadiene-3,20-di.one 21-acetate is used as starting material in the foregoing reaction with selenium dioxide and the product hydrolyzed with aqueous methanolic potassium bicarbonate solution, there are obtained 11fi,l7oc,21 trihydroxy 6,16a dimethyl 1,4,6- pregnatriene 3,20 dione and its 21 acetate. Where the starting material in this procedure is 115,17o,21 trihydroxy 6,165 dimethyl 4,6 pregnadiene 3, 20 dione 21-acetate, there are obtained 11fi,17 x,2l-trihydroxy 6,16,!3 dimethyl 1,4,6 pregnatriene 3,20- dione and its 21 acetate.

Where the starting material in the foregoing reaction With selenium dioxide followed by hydrolysis with aqueous methanolic potassium bicarbonate is 900 fluoro 11B, 17u,21 trihydroxy 6, 16a dimethyl 4,6 pregnadiene- 3,20-dione 21-acetate, the products obtained are 90:- fluoro 11B,17oc,2l trihydroxy 6,16a dimethyl 1,4,6- pregn-atriene 3,20 dione and its 21 acetate.

In accordance with the above procedure but starting with 9oc-Chl0r0-1 15,17u,21-trihydroxy-6,16ot-dimethyl-4,6- pregnadiene-3,30-dione 21-acetate there are obtained 90:- chloro llfi,l7a,21 trihydroxy 6,16a-dimethyl-1,4,6 pregnadiene-3,20-dione and its 2l-acetate.

Similarly, in accordance with the above procedure but starting with 9a-bromo 11B,17u,21 dihydroxy-6,160:- dimethyl-4,6-pregnadiene-3,ZO-dione 21-acetate there are obtained 90c bromo 11,8,17a,2l trihydroxy-6,16a-dimethyl-1,4,6-pregnatriene 3,20 dione and its 21-aeetate.

In accordance with the above procedure but starting With 90: fiuoro-l1fi,17a,21-trihydroxy-6,l6fi-dimethyl-4, 6-pregnadiene-3,20-dione 2l-acetate there are obtained 9w fluoro 11fi,17a,21 trihydroxy 6,16,8-dimethyl-l,4,6- pregnatriene-3,20-dione and its 21-acetate.

In accordance with the above procedure but starting with 9a-chloro-11,8,1706,21-trihydroxy-6,165-dimethyl-4,6- pregnadiene-3,20-dione 21-acetate there are obtained 9achloro 11,8,17a,21-trihydroxy 6,16B-dimethyl 1,4,6- pregnatriene-3,20-dione and its 21-acetate.

In accordance with the above procedure but starting with 9a-bromo-1 1fi,l7a,21-trihydroxy-6,16 8-dimethyl-4,6- pregnadiene-3,20-dione 21-acetate there are obtained 90cbromo 11,8,17oc,21 trihydroxy 6,16fi-dimethy11,4,6- pregnatriene-3,20-dione and its 21-acetate.

To a solution of 200 mg. of 9oa-flllOrO17o,21-dihydroxy-6,16oc-dimethyl-4,6-pregnadiene 3,11,20-trione 21- acetate in 0.16 ml. of acetic acid and 12 ml. of t-amyl alcohol is added 120 mg. of selenium dioxide and 2 drops of mercury. The mixture is refluxed under nitrogen overnight. The solution is filtered, washed with sodium bicarbonate, dried, and concentrated. This product is chromatographed on acid-washed alumina. The adsorbate is eluted with mixtures of chloroform and ether, increasingly rich in chloroform. The eluates are combined, evaporated to dryness and the residual material recrystallized from ethyl acetate to give 9a-flu0ro-17u,21- dihydroxy-6,16u-dimethyl 1,4,6-pregnatriene 3,11,20- trione 21-acetate. This product is then hydrolyzed by treatement with a solution of potassium bicarbonate in aqueous methanol to form 9a-fluoro-l7u,21-dihydroxy- 6,16a-dimethyl-1,4,6-pregnatriene-3 ,11,20-trione.

In accordance with the above procedure but starting with 9a-chloro-17u,2l-dihydroxy 6,16a-dimethyl 4,6- pregnadiene-3,11,20-trione 21-acetate there are obtained 9u-Chl010 170:,21 dihydroxy 6,16a-dimethyl-1,4,6 pregnatriene-3,11,20-trione and its 21-acetate.

Similarly, in accordance with the above procedure but starting with 9a-brom0-17a,21-dihydroxy-6,16a dimethyl- 4,6-pregnadiene-3,11,20-trione 21-acetate there are obtained 9a-bromo 1704,21 dihydroxy-6,16a-dimethyl-l, 4,6-pregnatriene-3,11,20-trione and its 21-acetate.

In accordance with the above procedure but starting with 9a-fluoro P 170:,21 dihydroxy-6,16,8-dimethyl-4,6-

32 pregnadiene-3,11,20-trione 21-acetate there are obtained 9oc-fluOIO-17a,2l dihydroxy 6,16fl-dimethyl 1,4,6- pregnatriene-3,11,20-trione and its 2l-acetate.

In accordance with the above procedure but starting with 9u-chloro 17a,21 dihydroxy-6,16B-dimethyl-4,6- pregnadiene-3,11,20 trione 2l-acetate there are obtained 9a-chloro-17ot,21-dihydroxy-6,16,8-dimethyl 1,4,6-pregnatriene-3,11,20-trione and its 21-acetate.

In accordance with the above procedure but starting with 9OL-bI'OIT1O 17:1,21 dihydroxy-6,16B-dimethyl-4,6- pregnadiene-3,11,20-trione 21-acetate there are obtained 9oc-bromo 17a,2l dihydroxy 6,16,8-dimethyl 1,4,6- pregnatriene-3,11,20-trione and its 2l-acetate.

To a suspension of 25.0 g. of 11fl,17a,21-trihydroxy- 6,l6a-dimethyl-4,6-pregnadiene-3,20-dione (which can be prepared as described in Example 3 hereinabove) in 1.5 l. of alcohol-free chloroform cooled to about 5 C. in an ice bath is added with constant stirring 750 ml. of cold, concentrated aqueous hydrochloric acid solution and then 750 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for approximately 7 hours. The layers are separated and the aqueous phase is back-extracted twice with chloroform. The combined chloroform layers are Washed twice with a 5% aqueous solution of sodium bicarbonate, and twice with a saturated aqueous solution of sodium chloride. The washed chloroform solution is dried over magnesium sulfate and evaporated under reduced pressure. The residual material is triturated with methanol to give a crystalline solid, which is recrystallized from a mixture of benzene and n-hexane to give :,20, 20,21 bismethylenedioxy 1lfl-hydroxy-6,l6ot-dimethyl- 4,6-pregnadiene-3-one.

A solution of 400 mg. of 17a,20,20,2l-bismethylenedioxy-llfi-hydroxy-6,16zx-dimethyl-4,6 pregnadiene 3- one in 4 ml of pyridine is added to the complex formed by the addition of 400 mg. of chromium trioxide to 4 ml. of pyridine. The mixture is swirled until thoroughly mixed and then allower to stand at room temperature for a period of about 15 hours. The reaction mixture is poured into Water, and the aqueous mixture is extracted with ether and then twice with ethyl acetate. The combined ether and ethyl acetate extracts are washed with dilute aqueous sulfuric acid at about 0 C., and then with Water until neutral. The organic solvent layer is then dried, the solvents are evaporated therefrom in vacuo, and the residual crystalline material is purified by crystallization from a mixture of ethyl acetate and ether to give 17oc,20,20,2l-bismethylene dioxy-6,l6u-dimethyl 4,6- pregnadiene-3,1l-dione.

Approximately 1.35 g. of 17a,20,20,2l-bismethylenedioxy-6,16a-dimethyl-4,6-pregnadiene-3,1l-dione is dis solved in 23 ml. of dry, hot benzene, the resulting solution is cooled to room temperature, and to the solution is added 0.96 ml. of freshly-distilled ethyl formate. The air in the system is replaced with nitrogen and 560 mg. of sodium hydride (as a 58% dispersion in mineral oil) is added. The system is again evacuated and filled with nitrogen, and the mixture is stirred at room temperature for a period of about 15 hours. The reaction mixture is poured into an excess of a saturated aqueous solution of sodium dihydrogen phosphate, and the resulting aqueous mixture is extracted four times with benzene. The benzene reaction solution and extracts are combined, washed three times with water, dried over sodium sulfate, and evaporated to dryness. The residual material is dissolved in ether, and the ether solution is extracted with a 10% aqueous solution of sodium carbonate. The aqueous alkaline extracts are acidified with an excess of a saturated aqueous solution of sodium dihydrogen phosphate, and the aqueous acidic mixture extracted with ether and then with chloroform. The combined organic extracts are dried over sodium sulfate, and evaporated to dryness to give 17a,20,20,2l-bismethylenedioxy- 33 Z-hydroxy methylene-6,16a-dimethyl-4,6 pregnadiene- 3,11-dione.

Approximately 850 mg. of 17a,20,20,2I-bismethylenedioxy-2-hydroxymethylene-6,16u-dimethyl 4,6 pregnadiene-3,11-dione is dissolved in 9.2 ml. of absolute ethanol, and to the solution is added a solution of 0.16 ml. of hydrazine hydrate dissolved in 0.16 ml. of absolute ethanol. The resulting mixture is heated under reflux in a nitrogen atmosphere for a period of about 45 minutes, and the reaction mixture is then evaporated to dryness under reduced pressure. The residual material is washed with three portions of cold water, and the resulting amorphous solid is dried at a temperature of about 80 C. for 1 hour in high vacuum to give 170:, 20,20,21 bismethylenedioxy 6,16a-dimethyl [3,2-c] pyrazolo-4,6-pregnadiene-1 1-one.

To a solution of 100 mg. of 17a,20,20,21-bismethylenedioxy-6,16a-dimethyl-[3,2-c] pyrazolo 4,6 pregnadiene-ll-one in 2 ml. of pyridine is added 0.5 ml. of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, with ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), with saturated aqueous sodium bicarbonate solution (until the pH of the aqueous layer is 8), and with water (until the aqueous layer is neutral). The ethyl acetate solution is then dried with anhydrous sodium sulfate, and the solvent is distilled at a temperature of about 40 C., in vacuo to give 1'-acetyl-17u,20, 20,2l-bismethylenedioxy-6,16ot-dimethyl [3,2-c] pyrazolo-4,6-pregnadiene-1l-one, which is isolated by the addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of the acetic anhydride, there is obtained the corresponding 1acyl derivative.

Approximately 720 mg. of 1-acetyl-17a,20,20,21-bismethylenedioxy 6,1604 dimethyl-[3,2-c] pyrazolo-4,6- pregnadiene-ll-one is heated on a steam bath with. 24 ml. of a 60% aqueous solution of formic acid for a period of about 30 minutes. The excess reagent is removed in vacuo using a water bath at a temperature of about 50 C. as the source of heat. The residual material is flushed four times with n-hexane, and dried at 60 C. in high vacuum. The amorphous solid thus obtained is dissolved in about 3.4 ml. of pure methanol and allowed to react with 1.3 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The excess sodium methoxide is neutralized with acetic acid, and the mixture is then evaporated to dryness and flushed with n-hexane. The residual material is washed with water, filtered and dried to give 17a,21-dihydroxy-6,16adimethyl-[3,2-c] pyrazolo-4,6-pregnadiene-11,20-dione.

In accordance with the above procedures, but starting with the 11B,17u,21-trihydr0xy-6,16,8-dimethyl-4,6-pregnadiene-3,20-dione (which can be prepared as described hereinabove) in place of the 11B,17a,21-trihydroxy- 6,16u-dimethyl-4,6-pregnadiene-3,20-dione, there is obtained as product the corresponding 17a,21-dihydroxy-6, 16B-dimethyl-[3,2-c] pyrazolo-4,6-pregnadiene 11,20- dione.

In accordance with the above procedures, but starting with 1*1B,17a,2l trihydroxy-6,16ot-dimethyl-9a-fluoro- 4,6-pregnadiene-3,20-dione (which can be prepared as described hereinabove) in place of the 11fi,17a,21-trihydroxy-6,16wdirnethyl-4,6-pregnadiene-3,20-dione, there is obtained as product, via the intermediate formation of 1'- acetyl 17oz,20,20,2l bismethylenedioxy-'6,l6a-dimethyl- 9a-fill0IO-[3,2-C] pyrazolo-4,6-pregnadiene-11 one, the corresponding 17a,21-dihydroxy-6,16tx-dimethyl-9a-fluoro [3,2-c] pyrazolo-4,6-pregnadiene-1 1,20-dione. Alternatively, the intermediate 1'-acetyl-17a,20,20,21-bismethylenedioxy 6,16a-dimethyl-9a-fluoro-[3,2-c] pyrazolo-4,6- pregnadiene-ll-one is reacted with sodium borohydride to form 1-acetyl-17a,20,20,2l-bismethylenedioxy 6,16oz-dimethyl-9a-fluoro-[3,2-c] pyrazolo 4,6-pregnadiene-11B- 01 which is then reacted with 60% aqueous formic acid and the resulting amorphous solid reacted with dilute methanolic sodium methoxide as described hereinabove in this example, thereby forming 11B,17u,21-tryhydroxy- 6,1604 dimethyl c fluoro-[3,2c] pyrazolo-4,6-pregnadiene-ZO-one.

Appropriately 1.35 g. of 17a,20,20,2l-bismethylenedioxy 1lfl-hydroxy-6,16a-dimethyl-4,6-pregnadiene-3-one (which can be prepared as described hereinabove in this example) is dissolved in 23 ml. of dry, hot benzene, the resulting solution is cooled to room temperature, and to the solution is added 0.96 ml. of freshly-distilled ethyl formate. The air in the system is replaced with nitrogen and 560 mg. of sodium hydride (as a 58% dispersion in mineral oil) is added. The system is again evacuated and filled with nitrogen, and the mixture is stirred at room temperature for a period of about 15 hours. The mixture is poured into an excess of a saturated aqueous solution of sodium dihydrogen phosphate, and the resulting aqueous mixture is extracted four times with benzene. The benzene reaction solution and extracts are combined, washed three times with water, dried over sodium sulfate, and evaporated to dryness. The residual material is dissolved in ether, and the ether solution is extracted with a 10% aqueous solution of sodium carbonate. The aqueous alkaline extracts are acidified with an excess of a saturated aqueous solution of sodium dihydrogen phosphate, and the aqueous acidic mixture extracted with ether and then with chloroform. The combined organic extracts are dried over sodium sulfate, and evaporated to dryness to give 17u,20,20,2l bismethylenedioxy llfi-hydroxy-Z-hydroXymethylene-6,16ot-dimethyl-4,6-pregnadiene-3-one.

Approximately 850 mg. of 17a,20,20,2l-bismethylenedioxy-11,B-hydroxy-2-hydroxymethylene 6,16a-dimethyl- 4,6-pregnadiene-3-one is dissolved in 9.2 ml. of absolute ethanol, and to the solution is added a solution of 0.16 ml. of hydrazine hydrate dissolved in 0.16 ml. of absolute ethanol. The resulting mixture is heated under reflux in a nitrogen atmosphere for a period of about 45 minutes, and the reaction mixture is then evaporated to dryness under reduced pressure. The residual material is washed with three portions of cold water, and the resulting amorphous solid is dried at a temperature of about 80 C. for 1 hour in high vacuum to give 17a,20,20,2l-bismethylenedioxy-6,160: dimethyl-[3,2-c] pyrazolo-4,6-pregnadiene- 1 16-01.

To a solution of mg. of 17a,20,20,2l-bismethylenedioxy 6, 16a-dimethyl-[3,2-c] pyrazolo-4,6-pregnadienellfl-ol in 2 ml. pyridine is added 0.5 ml. of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, with ice-cold 1 N sulfuric acid' (until the pH of the aqueous layer is 13), with saturated aqueous sodium bicarbonate solution (until the pH of the aqueous layer is 8), and with water (until the aqueous layer is neutral). The ethyl acetate solution is then dried with anhydrous sodium sulfate, and the solvent is distilled at a temperature of about 40 C. in vacuo to give 1'ace tyl 17a,20,20,21 bismethylenedioxy 6,16a dimethyl-' about 30 minutes. The excess reagent is removed in vacuo using a Water bath at a temperature of about 50 C. as the source of heat. The residual material is flushed four times with n-hexane, and dried at 60 C. in high vacuum. The amorphous solid thus obtained is dissolved in about 3.4 ml. of pure methanol and allowed to react with 1.3 ml. of a 1.33 N solution of sodium rnethoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The excess sodium rnethoxide is neutralized with acetic acid, and the mixture is then evaporated to dryness and flushed with n-hexane. The residual material is washed with water, filtered and dried to give 11B,'17a,21- trihydroxy 6,16a-dimethyl-[3,2-c] pyrazolo-4,6-pregnadiene-ZO-one.

Approximately 0.5 g. of l7a,20,20,2l-bismethylenedioxy-l 1,8-hydroxy-6,16a-dimethyl-4,6-p.regnadiene-3-one is dissolved in 25 cc. of benzene, and about 5 cc. of benzene is removed from the solution by distillation at normal pressure. The resulting solution is cooled to room temperature, and to the solution is added about 0.75 cc. of freshly-distilled ethyl formate. The air in the system is replaced With nitrogen, and about 150 mg. of sodium hydride (as a 57% dispersion in mineral oil) is added. The mixture is stirred under nitrogen at room temperature for a period of about three hours. About cc. of a saturated aqueous solution sodium dihydrogen phosphate is added to the reaction mixture and the resulting aqueous mixture is extracted with ether. The benzene solution and ether extracts are combined, extracted with 2 N aqueous sodium hydroxide, and the aqueous sodium hydroxide extracts are acidified with sodium dihydrogen phosphate. The aqueous acidified solution is extracted with ether, the ether extract is evaporated to dryness, and the residual material is crystallized from ether to give l7a,20,20,2l-bismethylenedioxy-l 1B formyloxy-Z-hydroxymethyleue-6,16a-dimethyl- 4,6-pregnadiene-3-one. Evaporation of the ether mother liquor, followed by recrystallization of the residual material from ether gives substantially pure l7a,20,20,2l-bismethylenedioxy 11,8 hydroxy 2 hydroxymethyleue- 6,16a-dimethyl-4,6-pregnadiene-3-one; M.P. 200-204 C.

Approximately 1.19 g. of 17a,20,20,2l-bismethylenedioxy-l1fl-hydroxy-Z-hydroxymethylene-6,16a dimethyl- 4,6-pregnadiene-3-one is dissolved in cc. of ethanol. Three hundred mg. of phenyl hydrazine is added, and the mixture is heated under reflux in a nitrogen atmosphere for one hour. About 25 cc. of Water is added. The product is then extracted into 150 cc. of ether. The ether extracts are washed with 2 N aqueous HCl, with saturated sodium bicarbonate, with water, with saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The washed and dried ether extracts are evaporated to dryness and the residual material is crystallized from ether to give 17a,20,20,21-bismethylenedioxy-6,16or-dimethyl-2'-phenyl [3,2-0] pyrazolo-4,6-pregnadiene-1113-01; M.P. 258262 C.

Approximately 430 mg. of 17a,20,20,21-bismethylenedioxy-6,16o-dimethyl 2' phenyl-[3,2-c]pyrazolo-4,6- pregnadiene-llB-ol is heated on a steam bath under nitrogen with 40 cc. of a 60% aqueous solution of formic acid for a period of about minutes. About cc. of water is added to the reaction mixture, and the mixture is then extracted into about 200 cc. of chloroform. The chloroform solution is Washed with water, with saturated aqueous sodium bicarbonate solution, again with water, and is then dried over anhydrous sodium sulfate. The washed and dried chloroform solution is evaporated under vacuum and the residual product is dissolved in cc. of absolute methanol, and 0.1 equivalent of sodium rnethoxide in methanol is added. The resulting mixture is stirred under nitrogen at room temperature for 15 minutes. The reaction mixture is acidified with acetic acid, and the solvent is evaporated under vacuum at room temperature. Above 20 cc. of water is added to the residual material, and the aqueous mixture is extracted with about 150 cc. of ethyl acetate. The ethyl acetate solution is washed with saturated aqueous sodium bicarbonate solution, with water, and is then dried over anhydrous sodium sulfate and evaporated to dryness to give an amorphous solid. This amorphous solid is dried in a high vacuum, and is then dissolved in 4 cc. of pyridine. About 3 cc. of acetic anhydride is added. The resulting mixture is heated on the steam bath for about 15 minutes and evaporated to dryness in vacuo. About 20 cc. of water is added. The aqueous mixture is then extracted with about 150 cc. of ethyl acetate, the ethyl acetate extract is Washed with saturated aqueous sodium bicarbonate solution, and with Water, and is then dried over anhydrous sodium sulfate. The washed and dried ethyl acetate solution is evaporated in vacuo, and the residual material is crystallized from ethyl acetatebenzene to give substantially pure 11B,17a,21-trihydroxy- 6,160; dimethyl 2' phenyl [3,2-c]pyrazolo 4,6- pregnadiene-20-one 21-acetate; M.P. 225226 C.

One hundred mg. of 11B,17a,21-trihydroxy-6,16adimethyl 2' phenyl-[3,2-c]pyrazolo-4,6-pregnadiene-20- one 21-acetate is dissolved in 10 cc. of absolute methanol, and 1.1 equivalents of sodium rnethoxide in methanol is added. The mixture is stirred at room temperature under nitrogen for 15 minutes. The product is acidified with acetic acid and is then evaporated at room temperature under vacuum. The residual material is dissolved in cc. of chloroform, the chloroform solution is washed with water, with saturated aqueous sodium bicarbonate solution, again with water, and is then dried over anhydrous sodium sulfate. The Washed and dried chloroform solution is evaporated to dryness to give 11,8,17rx,21- trihydroxy 6,16a dimethyl-2'-phenyl-[3,2-c]pyrazolo 4,6-pregnadiene-20-one.

Various changes and modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the purview of the annexed claims, they are to be considered as part of our invention.

We claim:

1. 21-galacturonides of Ring A unsaturated 11,17-bisoxygenated-20-keto-steroids of the anti-inflammatory 2lhydroxy pregnanes.

2. Sodium salt of 11,8,l7u,21-trihydroxy-1,4-pregnadiene-3,20-dione 2l-galacturonide.

3. Sodium salt of 16rx-methyl-11r3,17a,21trihydroxy-4- pregnene-3,20-dione 21-galacturonide.

4. Sodium salt of 16or-methyl-11,8,17a,2l-trihydroxy- 1,4-pregnadiene-3,20-dione 21-galacturonide.

5. Sodium salt of 9a-fluoro-16a-methyl-1l5,l7a,21-trihydroxy-1,4-pregnadiene-3,20-dione 2l-galacturonide.

6. Sodium salt of 9a-fluoro-16fi-methyl-115,17u,21-trihydroxy-1,4-pregnadiene-3,20-dione 2 l-galacturonide.

7. Sodium salt of 6wmethyl-11,8,17a,21-trihydroxy-l,4- pregnadiene-3,20-dione 21-galacturonide.

8. Sodium salt of a 6a-fluoro-11fl,17a,21-trihydroxy- 1,4-pregnadiene-3,20-dione 21-galacturonide.

9. Sodium salt of 6,16a-dimethyl 11fi,17rx,Z1-trihydroxy-4,6-pregnadiene-3,20-dio ne 21-galacturonide.

10. A compound selected from the group consisting of 9a-fiuoro,115,1611,17u,21-tetrahydroxy 1,4-pregnadiene- 3,20-dione 21-galacturonide, the 16,17-acetonide thereof, and pharmacologically acceptable salts of the foregoing.

11. Sodium salt of 6,16u-dimethyl-l1B,17a,21-trihydroxy- 3,2-c] pyrazolo-4,6-pregnadiene-20-one 21-galactu-- ronide.

12. Sodium salt of 6,16a-dimethyl-11,8,17a,21-trihydroxy-2-phenyl-[3,2-c]pyrazolo-4,6-pregnadiene 20-one 21-galacturonide.

13. Methyl (11B,17u-dihydroxy 1,4-pregnadiene-3,20- dione 21-yl tri-O-acetyl-B-D-galactopyranosid)-uronate.

14. Methyl (16a-methyl-115,17u-dihydroxy-4-pregnene- 3,20-dione-21-yl tri-O-acetyl-B-D-galactopyranosid)-uronate.

15. Methyl (16a-methyl-11fi,17a-dihydroxy-L4-pregnadiene-3,20-dione-21-y1 tri-O-acetyl-B-D-galactopyranosid)- uronate.

18. A composition for injection administration comprising a 21-galacturonide of a Ring A unsaturated 11,17- bis-oxygenated-ZO-keto-steroid of the anti-inflammatory 21-hydroxy pregnanes dispersed in a pharmacologically 1,4-pregnadiene-3,20-dione-21-y1 tri-O-acetyl-fl-D-galacto- 5 acceptable liquid carrier.

pyranosid)-uronate.

17. Methyl (6,16a-dimethyl-1lfi,17a-dihydroxy-[3,2-c] pyrazolo-4,6-pregnadiene 20-one-21-y1 tri-O-acetyl-fl-D- galactopyranosid)-uronate.

No references cited LEWIS GOTTS, Primary Examiner. 

1. 21-GALACTURONIDES OF RING A UNSATURATED 11,17-BISOXYGENATED-KETO-STEROIDS OF THE ANTI-INFLAMMATORY 21HYROXY PREGNANES.
 18. A COMPOSITION FOR INJECTION ADMINSITRATION COMPRISING A 21-GALACTURONIDE OF A RING A UNSATURATED 11,17BIS-OXYGENATED-20-KETO-STEROID OF THE ANTI-INFLAMMATORY 21-HYDROXY PREGNANES DISPERSED IN PHARMACOLOGICALLY ACCEPTABLE LIQUID CARRIER. 